Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation ...Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation in higher vertebrates,its roles in fish are not well understood.This study established hypoxia-induced models in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the involvement of IL-22 in maintaining intestinal homeostasis.Results revealed that Pelteobagrus fulvidraco IL-22(Pf_IL-22)was abundantly expressed in mucosal tissues,with the highest levels in the gill and intestine.Hypoxia induced pronounced intestinal injury,characterized by loosening of the lamina propria and extensive vacuolization,while activating hypoxia-inducible factor(HIF)signaling and markedly up-regulating IL-22 expression.IL-22 levels peaked at 24 h post-hypoxia,suggesting a role in early immune responses.Recombinant Pf_IL-22 also induced transcription of pro-inflammatory mediators,including IL-1βand tumor necrosis factorα(TNF-α),in primary intestinal epithelial cells,indicating a dual regulatory function in balancing protection and inflammation.Mechanistic analyses revealed that HIF-1αdirectly interacted with a hypoxia response element within the IL-22 promoter to drive transcription,as confirmed by dual-luciferase assays,electrophoretic mobility-shift assays,and HIF-1αknockdown.Silencing Pf_IL-22 significantly suppressed Th17 cell differentiation pathways,demonstrating its role in shaping downstream immune responses.These findings establish the HIF-1α/IL-22 axis as a key regulatory pathway modulating immune responses and alleviating intestinal inflammation,providing a basis for developing IL-22-targeted immunotherapies and selective breeding strategies in aquaculture.展开更多
BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasi...BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasis.However,the precise function of IL-22 in colorectal cancer(CRC)remains unclear.AIM To investigate the role of IL-22 in promoting stem cell-like characteristics and chemotherapy resistance in CRC cells,as well as to elucidate the mechanisms underlying these effects.METHODS HCT116 cells were treated with IL-22(50 ng/mL)and oxaliplatin(L-OHP,5μg/mL).A series of functional assays-including cell counting kit-8 assay,tumor sphere formation assay,and cell apoptosis assay-were conducted to assess the effects of IL-22 on cell viability and stem cell-like characteristics.The expression of stemness-related markers(SOX2,Oct4,NANOG,and Bmi-1)was examined using Western blot analysis.Additionally,the total and phosphorylated levels of epidermal growth factor receptor(EGFR),protein kinase B(AKT),and extracellular signal-regulated kinase(ERK)were evaluated by Western blot.An EGFR inhibitor,osimertinib(Osi),was used to assess the pathway's functional relevance.RESULTS IL-22 treatment promotes CRC cell proliferation,enhances sphere formation,and elevates the expression of stem cell markers,including SOX2,Oct4,NANOG,and Bmi-1.IL-22 treatment increases the phosphorylation of EGFR,AKT,and ERK.Additionally,IL-22 treatment mitigates the cytotoxic effects and the ability to induce apoptosis of L-OHP.Furthermore,IL-22 treatment activated the EGFR/ERK signaling pathway by increasing the phosphorylation of EGFR,AKT,and ERK.Importantly,the use of the EGFR inhibitor Osi significantly counteracted the chemoresistance induced by IL-22 in CRC cells.CONCLUSION IL-22 promotes tumor growth and induces chemotherapy resistance in CRC cells by activating the EGFR/ERK signaling pathway.These findings suggest that targeting IL-22 or its downstream signaling may offer novel therapeutic strategies in CRC.展开更多
AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained fr...AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p- STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS:Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3-positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated.CONCLUSION:IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC.展开更多
BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regen...BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regeneration.It has been reported that vagus nerve signaling is beneficial to liver regeneration,but the potential mechanism at play here is not fully understood.AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.METHODS A PHx plus hepatic vagotomy(Hv)mouse model was established.The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice.In order to further investigate the role of interleukin(IL)-22 in liver regeneration inhibition mediated by Hv,the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured.The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.RESULTS Compared to control-group mice,Hv mice showed severe liver injury and weakened liver regeneration after PHx.Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3(STAT3)pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx.Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury,while treatment with IL-22 binding protein(an inhibitor of IL-22 signaling)reduce the concentration of IL-22 induced by PHx,inhibits the activation of the STAT3 signaling pathway in the liver after PHx,thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.CONCLUSION Hv attenuates liver regeneration after hepatectomy,and the mechanism may be related to the fact that Hv downregulates the production of IL-22,then blocks activation of the STAT3 pathway.展开更多
AIM: To investigate the potential protective effect of exogenous recombinant interleukin-22(r IL-22) on L-arginine-induced acute severe pancreatitis(SAP)-associated lung injury and the possible signaling pathway invol...AIM: To investigate the potential protective effect of exogenous recombinant interleukin-22(r IL-22) on L-arginine-induced acute severe pancreatitis(SAP)-associated lung injury and the possible signaling pathway involved.METHODS: Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase(MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin(HE) staining. Expression of B cell lymphoma/leukemia-2(Bcl-2), Bcl-x L and IL-22RA1 m RNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS: Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group(P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-x L m RNAs in the SAP group was decreased markedly, while the IL-22RA1 m RNA expression was increased significantly relative to the normal control group(P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-x L or IL-22RA1 m RNA(P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the r IL-22 group were significantly lower than those in the SAP group(P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, r IL-22 stimulated the expression of Bcl-2, Bcl-x L and IL-22RA1 m RNAs in the lung(P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the r IL-22 group was significantly higher than that in the PBS group(P < 0.05).CONCLUSION: Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.展开更多
AIM: To investigate the therapeutic effects and mechanisms of interleukin(IL)-22 in liver regeneration in mice with concanavalin A(Con A)-induced liver injury following 70% hepatectomy.METHODS: Mice were injected intr...AIM: To investigate the therapeutic effects and mechanisms of interleukin(IL)-22 in liver regeneration in mice with concanavalin A(Con A)-induced liver injury following 70% hepatectomy.METHODS: Mice were injected intravenously with Con A at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline.RESULTS: IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3(STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein m RNA expression was significantly elevated after IL-22 treatment.CONCLUSION: In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.展开更多
BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in ge...BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.展开更多
Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and ...Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin(IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly antiinflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the antiautophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.展开更多
Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of ...Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.展开更多
In order to study the expression of interleukin-22 （IL-22） and S 100A7, A8, A9 mRNA in the skin lesions of patients with psoriasis vulgaris and their relationship, the biopsies were taken from skin lesions in 35 pat...In order to study the expression of interleukin-22 （IL-22） and S 100A7, A8, A9 mRNA in the skin lesions of patients with psoriasis vulgaris and their relationship, the biopsies were taken from skin lesions in 35 patients with psoriasis vulgaris and the skin of 16 normal controls, and the expression levels of 1L-22 and S 100A7, A8 and A9 mRNA were detected by semi-quantitative RT-PCR. The results showed that （1） IL-22 and S 100A8, A9 mRNA were positively expressed in the psoriatic skin lesions but negatively expressed in the normal controls; The expression level of S 100A7 was （1.133±0.040） in the psoriatic skin lesions, significantly higher than that in the normal controls （0.744±0.037, P〈0.01）. （2） There were significantly positive correlations between the expression of IL-22/S100A7 mRNA, IL-22/S100A8 mRNA, IL-22/S100A9 mRNA in the psoriasis vulgaris （r1=-0.543, r2=0.774, r3=0.621, P〈0.01）. It was concluded that IL-22 and S 100A7, A8, A9 might play important roles in the occurrence and progression of psoriasis.展开更多
AIM:To investigate the effect of interleukin(IL)-22 onhepatic fibrosis in mice and the possible mechanism involved.METHODS:Liver fibrosis was induced in male BALB/c mice by CCl4.Recombinant IL-22(rm IL-22) was adminis...AIM:To investigate the effect of interleukin(IL)-22 onhepatic fibrosis in mice and the possible mechanism involved.METHODS:Liver fibrosis was induced in male BALB/c mice by CCl4.Recombinant IL-22(rm IL-22) was administered intraperitoneally in CCl4-treated mice.Fibrosis was assessed by histology and Masson staining.The activation of hepatic stellate cells(HSCs) was investigated by analysis of α-smooth muscle actin expression.The frequencies of T helper(Th) 22 cells,Th17 cells and Th1 cells,the expression of inflammatory cytokines [IL-22,IL-17 A,interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),IL-6,IL-1b] and transcription factors [aryl hydrocarbon receptor(AHR),RAR-related orphan receptor(RORγt),T-bet] m RNA in the liver were investigated.In addition,the plasma levels of IL-22,IL-17 A,IFN-γ,TNF-α,IL-6 and IL-1b were evaluated.RESULTS:Significant elevations in circulating Th22 cells,Th17 cells,Th1 cells,IL-22,IL-17 A,and IFN-γ were observed in the hepatic fibrosis group compared with the control group(P < 0.01).Treatment with rm IL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis,which was confirmed by lower hepatic fibrosis pathological scores(P < 0.01).Rm IL-22 decreased the frequencies of Th22 cells(6.71% ± 0.97% vs 8.09% ± 0.74%,P < 0.01),Th17 cells(4.34% ± 0.37% vs 5.71% ± 0.24%,P < 0.01),Th1 cells(3.09% ± 0.49% vs 4.91% ± 0.73%,P < 0.01),and the levels of IL-22(56.23 ± 3.08 vs 70.29 ± 3.01,P < 0.01),IL-17A(30.74 ± 2.77 vs 45.68 ± 2.71,P < 0.01),and IFN-γ(74.78 ± 2.61 vs 124.89 ± 2.82,P < 0.01).Down-regulation of IL-22,IL-17 A,IFN-γ,TNF-α,IL-6,IL-1b,AHR RORγt,and T-bet gene expression in the liver was observed in the rm IL-22 group(P < 0.01).CONCLUSION:The frequencies of Th22,Th17 andTh1 cells are elevated in hepatic fibrosis.Rm IL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines,thereby ameliorating liver fibrogenesis.展开更多
Objective:To observe the effects of interleukin-22(IL-22)on the expression of type Ⅲ collagen,cytokines,growth factors and chemokines in mouse cardiac fibroblasts in vitro.Methods:Mouse cardiac fibroblasts were treat...Objective:To observe the effects of interleukin-22(IL-22)on the expression of type Ⅲ collagen,cytokines,growth factors and chemokines in mouse cardiac fibroblasts in vitro.Methods:Mouse cardiac fibroblasts were treated with0μg/L(control),1μg/L(low concentration)and 100μg/L(high concentration)IL-22,respectively.In addition,cells treated with 100μmol/L static(an STAT3 pathway inhibitor)and 100μg/L IL-22 was defined as the block group.After treatment for 48 hours,the mRNA level of collagen type Ⅲ A1(Col3-A1),matrix metalloproteinase-1(Timp-1),IL-22receptor(IL-22R),interleukin 10-related T cellderived inducible factor beta(Iltifb),fibroblast growth factor1(Fgf1)and C-C motif chemokine ligand 4(Ccl4)were determined by RT-PCR.The expression of Col3-A1 in cardiac fibroblasts was also semi-quantified by immunofluorescence.Results:Expression of Col3-A1 decreased in the low and high concentration groups,but significantly increased in the block group(all P <0.05).The expression of Timp-1increased in the low,high concentration and block groups compared with that in the control group,but it was significantly lower in the high concentration group than that in the low concentration group(P <0.05).The expression of IL-22 Rand Iltifb was significantly increased in the low,high concentration and block groups compared with that in the control group(P <0.05),but there was no statistical difference between the high concentration group and block group.The expression of Fgf1 and Ccl4 was significantly decreased in the low,high concentration and block groups compared with that in the control group(P <0.05),but there was no statistic difference between the high concentration group and block group as well.Conclusion:IL-22 effected on the expression of Col3-A1 and Timp-1,which was possibly through the JAK-STAT3 signaling pathway in mice cardiac fibroblasts.展开更多
The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multi...The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.展开更多
Diabetic nephropathy(DN)is considered the primary causes of end-stage renal disease(ESRD)and is related to abnormal glycolipid metabolism,hemodynamic abnormalities,oxidative stress and chronic inflammation.Antagonism ...Diabetic nephropathy(DN)is considered the primary causes of end-stage renal disease(ESRD)and is related to abnormal glycolipid metabolism,hemodynamic abnormalities,oxidative stress and chronic inflammation.Antagonism of vascular endothelial growth factor B(VEGF-B)could effi-ciently ameliorate DN by reducing renal lipotoxicity.However,this pharmacological strategy is far from satisfactory,as it ignores numerous pathogenic factors,including anomalous reactive oxygen species(ROS)generation and inflammatory responses.We found that the upregulation of VEGF-B and downregulation of interleukin-22(IL-22)among DN patients were significantly associated with the progression of DN.Thus,we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS.To meet these challenges,a novel anti-VEGFB/IL22 fusion protein was developed,and its therapeutic effects on DN were further studied.We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction.Moreover,the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity.Collectively,our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN,which highlighted a novel therapeutic approach to DN.展开更多
F-652 is a recombinant fusion protein consisting of two human interleukin-22(IL-22)molecules linked to an immunoglobulin constant region(IgG 2-Fc).IL-22 plays critical roles in promoting tissue repair and suppressing ...F-652 is a recombinant fusion protein consisting of two human interleukin-22(IL-22)molecules linked to an immunoglobulin constant region(IgG 2-Fc).IL-22 plays critical roles in promoting tissue repair and suppressing bacterial infection.The safety,pharmacokinetics(PK),tolerability,and biomarkers of F-652 were evaluated following a single dose in healthy male volunteers in a randomized,double-blind,placebo-controlled study.Following single-dose subcutaneous(SC)injection of F-652 at 2.0µg/kg into healthy subjects,six out of six subjects experienced delayed injection site reactions,which presented as erythematous and/or discoid eczematous lesions 10 to 17 days post-dosing.F-652 was then administered to the healthy subjects via an intravenous(IV)infusion at 2.0,10,30,and 45µg/kg.No severe adverse event(SAE)was observed during the study.Among the IV-dosed cohorts,eye and skin treatment emergent adverse events(TEAEs)were observed in the 30 and 45µg/kg cohorts.F-652 IV dosing resulted in linear increases in C max and AUC(0–t),and the T 1/2 ranged from 39.4 to 206h in the cohorts.An IV injection of F-652 induced dose-dependent increases in serum marker serum amyloid A,C-reactive protein,and FIB,and decreased serum triglycerides.The serum levels of 36 common pro-inflammatory cytokines/chemokines were not altered by the treatment of F-652 at 45μg/kg.In conclusion,IV administration of F-652 to healthy male volunteers is safe and well-tolerated and demonstrates favorable PK and pharmacodynamic properties.These results warrant further clinical development of F-652 to treat inflammatory diseases.展开更多
Background:In Type 1 diabetes,the insulin-producingβ-cells within the pancreatic islets of Langerhans are destroyed.We showed previously that immunotherapy with Bacillus Calmette-Guerin(BCG)or complete Freund’s adju...Background:In Type 1 diabetes,the insulin-producingβ-cells within the pancreatic islets of Langerhans are destroyed.We showed previously that immunotherapy with Bacillus Calmette-Guerin(BCG)or complete Freund’s adjuvant(CFA)of non-obese diabetic(NOD)mice can prevent disease process and pancreaticβ-cell loss.This was associated with increased islet Regenerating(Reg)genes expression,and elevated IL-22-producing Th17 T-cells in the pancreas.Results:We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas.We therefore quantified the Reg1,Reg2,and Reg3δ(INGAP)mRNA expression in isolated pre-diabetic NOD islets treated with IL-22.We measured IL-22,and IL-22 receptor(R)-αmRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice.Our results showed:1)Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro;2)IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment;3)a reduced expression of IL-22Rαfollowing CFA treatment;4)a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody;and 5)an increased isletβ-cell DNA synthesis in vitro in the presence of IL-22.Conclusions:We conclude that IL-22 may contribute to the regeneration ofβ-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.展开更多
基金supported by the National Natural Science Foundation of China(32102760)“JBGS”Project of Seed Industry Revitalization in Jiangsu Province(JBGS(2021)034)+1 种基金Creation Project of Major New Species of Agriculture in Jiangsu Province(PZCZ201742)Key Laboratory of Healthy Freshwater Aquaculture,Ministry of Agriculture and Rural Affairs,Key Laboratory of Freshwater Aquaculture Genetic and Breeding of Zhejiang Province,Zhejiang Institute of Freshwater Fisheries,Huzhou 313001(ZJK202404)。
文摘Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation in higher vertebrates,its roles in fish are not well understood.This study established hypoxia-induced models in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the involvement of IL-22 in maintaining intestinal homeostasis.Results revealed that Pelteobagrus fulvidraco IL-22(Pf_IL-22)was abundantly expressed in mucosal tissues,with the highest levels in the gill and intestine.Hypoxia induced pronounced intestinal injury,characterized by loosening of the lamina propria and extensive vacuolization,while activating hypoxia-inducible factor(HIF)signaling and markedly up-regulating IL-22 expression.IL-22 levels peaked at 24 h post-hypoxia,suggesting a role in early immune responses.Recombinant Pf_IL-22 also induced transcription of pro-inflammatory mediators,including IL-1βand tumor necrosis factorα(TNF-α),in primary intestinal epithelial cells,indicating a dual regulatory function in balancing protection and inflammation.Mechanistic analyses revealed that HIF-1αdirectly interacted with a hypoxia response element within the IL-22 promoter to drive transcription,as confirmed by dual-luciferase assays,electrophoretic mobility-shift assays,and HIF-1αknockdown.Silencing Pf_IL-22 significantly suppressed Th17 cell differentiation pathways,demonstrating its role in shaping downstream immune responses.These findings establish the HIF-1α/IL-22 axis as a key regulatory pathway modulating immune responses and alleviating intestinal inflammation,providing a basis for developing IL-22-targeted immunotherapies and selective breeding strategies in aquaculture.
文摘BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasis.However,the precise function of IL-22 in colorectal cancer(CRC)remains unclear.AIM To investigate the role of IL-22 in promoting stem cell-like characteristics and chemotherapy resistance in CRC cells,as well as to elucidate the mechanisms underlying these effects.METHODS HCT116 cells were treated with IL-22(50 ng/mL)and oxaliplatin(L-OHP,5μg/mL).A series of functional assays-including cell counting kit-8 assay,tumor sphere formation assay,and cell apoptosis assay-were conducted to assess the effects of IL-22 on cell viability and stem cell-like characteristics.The expression of stemness-related markers(SOX2,Oct4,NANOG,and Bmi-1)was examined using Western blot analysis.Additionally,the total and phosphorylated levels of epidermal growth factor receptor(EGFR),protein kinase B(AKT),and extracellular signal-regulated kinase(ERK)were evaluated by Western blot.An EGFR inhibitor,osimertinib(Osi),was used to assess the pathway's functional relevance.RESULTS IL-22 treatment promotes CRC cell proliferation,enhances sphere formation,and elevates the expression of stem cell markers,including SOX2,Oct4,NANOG,and Bmi-1.IL-22 treatment increases the phosphorylation of EGFR,AKT,and ERK.Additionally,IL-22 treatment mitigates the cytotoxic effects and the ability to induce apoptosis of L-OHP.Furthermore,IL-22 treatment activated the EGFR/ERK signaling pathway by increasing the phosphorylation of EGFR,AKT,and ERK.Importantly,the use of the EGFR inhibitor Osi significantly counteracted the chemoresistance induced by IL-22 in CRC cells.CONCLUSION IL-22 promotes tumor growth and induces chemotherapy resistance in CRC cells by activating the EGFR/ERK signaling pathway.These findings suggest that targeting IL-22 or its downstream signaling may offer novel therapeutic strategies in CRC.
基金Supported by National Natural Science Foundation of China,No.81072692Natural Science Foundation of Jiangsu Higher Education Institutions of China,No.10KJB320007
文摘AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p- STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS:Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3-positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated.CONCLUSION:IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC.
基金Supported by the Natural Science Foundation of Zhejiang Province,No.LQ20H310002the Scientific Technology Projects of Health and Medicine of Zhejiang Province,No.2020KY308and the Huzhou Science and Technology Fund,No.2020GY39.
文摘BACKGROUND Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy(PHx).At present,there is a lack of recognized safe,effective,and stable drugs to promote liver regeneration.It has been reported that vagus nerve signaling is beneficial to liver regeneration,but the potential mechanism at play here is not fully understood.AIM To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.METHODS A PHx plus hepatic vagotomy(Hv)mouse model was established.The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice.In order to further investigate the role of interleukin(IL)-22 in liver regeneration inhibition mediated by Hv,the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured.The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.RESULTS Compared to control-group mice,Hv mice showed severe liver injury and weakened liver regeneration after PHx.Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3(STAT3)pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx.Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury,while treatment with IL-22 binding protein(an inhibitor of IL-22 signaling)reduce the concentration of IL-22 induced by PHx,inhibits the activation of the STAT3 signaling pathway in the liver after PHx,thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.CONCLUSION Hv attenuates liver regeneration after hepatectomy,and the mechanism may be related to the fact that Hv downregulates the production of IL-22,then blocks activation of the STAT3 pathway.
基金Supported by the Shandong Provincial Science and TechnologyCommittee of China,No.2014GGH218034
文摘AIM: To investigate the potential protective effect of exogenous recombinant interleukin-22(r IL-22) on L-arginine-induced acute severe pancreatitis(SAP)-associated lung injury and the possible signaling pathway involved.METHODS: Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase(MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin(HE) staining. Expression of B cell lymphoma/leukemia-2(Bcl-2), Bcl-x L and IL-22RA1 m RNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS: Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group(P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-x L m RNAs in the SAP group was decreased markedly, while the IL-22RA1 m RNA expression was increased significantly relative to the normal control group(P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-x L or IL-22RA1 m RNA(P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the r IL-22 group were significantly lower than those in the SAP group(P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, r IL-22 stimulated the expression of Bcl-2, Bcl-x L and IL-22RA1 m RNAs in the lung(P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the r IL-22 group was significantly higher than that in the PBS group(P < 0.05).CONCLUSION: Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.
基金Supported by National Natural Science Foundation of ChinaNo.81370576+2 种基金Application Foundation and Advanced Technology Research Plan of TianjinChinaNo.14JCYBJC24800
文摘AIM: To investigate the therapeutic effects and mechanisms of interleukin(IL)-22 in liver regeneration in mice with concanavalin A(Con A)-induced liver injury following 70% hepatectomy.METHODS: Mice were injected intravenously with Con A at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline.RESULTS: IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3(STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein m RNA expression was significantly elevated after IL-22 treatment.CONCLUSION: In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.
基金Supported by Key R&D Plan of Science and Technology Department of Jiangxi Province,No.20171BBG70087
文摘BACKGROUND It is challenging to distinguish intestinal tuberculosis from Crohn’s disease due to dynamic changes in epidemiology and similar clinical characteristics. Recent studies have shown that polymorphisms in genes involved in the interleukin (IL)- 23/IL-17 axis may affect intestinal mucosal immunity by affecting the differentiation of Th17 cells. AIM To investigate the specific single-nucleotide polymorphisms (SNPs) in genes involved in the IL-23/IL-17 axis and possible pathways that affect susceptibility to intestinal tuberculosis and Crohn's disease. METHODS We analysed 133 patients with intestinal tuberculosis, 128 with Crohn’s disease, and 500 normal controls. DNA was extracted from paraffin-embedded specimens or whole blood. Four SNPs in the IL23/Th17 axis (IL22 rs2227473, IL1β rs1143627, TGFβ rs4803455, and IL17 rs8193036) were genotyped with TaqMan assays. The transcriptional activity levels of different genotypes of rs2227473 were detected by dual luciferase reporter gene assay. The expression of IL-22R1 in different intestinal diseases was detected by immunohistochemistry. RESULTS The A allele frequency of rs2227473 (P = 0.030, odds ratio = 0.60, 95% confidence interval: 0.37-0.95) showed an abnormal distribution between intestinal tuberculosis and healthy controls. The presence of the A allele was associated with a higher IL-22 transcriptional activity (P < 0.05). In addition, IL-22R1 was expressed in intestinal lymphoid tissues, especially under conditions of intestinal tuberculosis, and highly expressed in macrophage-derived Langhans giant cells. The results of immunohistochemistry showed that the expression of IL-22R1 in patients with Crohn's disease and intestinal tuberculosis was significantly higher than that in patients with intestinal polyps and colon cancer (P < 0.01). CONCLUSION High IL-22 expression seems to be a protective factor for intestinal tuberculosis. IL-22R1 is expressed in Langhans giant cells, suggesting that the IL-22/IL-22R1 system links adaptive and innate immunity.
文摘Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin(IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly antiinflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the antiautophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.
基金Supported by National Natural Science Foundation of China,No.81070288 and No.81270452Medical Science and Technology Foundation of Henan Province,No.201001004Science and Technology Leader Overseas Training Foundation of Henan Province,No.201201013
文摘Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses. Aberrant immune responses can cause secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract, leading to further inflammation. Interleukin (IL)-22 is a member of the IL-10 family of cytokines that was recently discovered to be mainly produced by both adaptive and innate immune cells. Several cytokines and many of the transcriptional factors and T regulatory cells are known to regulate IL-22 expression through activation of signal transducer and activator of transcription 3 signaling cascades. This cytokine induces antimicrobial molecules and proliferative and antiapoptotic pathways, which help prevent tissue damage and aid in its repair. All of these processes play a beneficial role in IBD by enhancing intestinal barrier integrity and epithelial innate immunity. In this review, we discuss recent progress in the involvement of IL-22 in the pathogenesis of IBD, as well as its therapeutic potential.
文摘In order to study the expression of interleukin-22 （IL-22） and S 100A7, A8, A9 mRNA in the skin lesions of patients with psoriasis vulgaris and their relationship, the biopsies were taken from skin lesions in 35 patients with psoriasis vulgaris and the skin of 16 normal controls, and the expression levels of 1L-22 and S 100A7, A8 and A9 mRNA were detected by semi-quantitative RT-PCR. The results showed that （1） IL-22 and S 100A8, A9 mRNA were positively expressed in the psoriatic skin lesions but negatively expressed in the normal controls; The expression level of S 100A7 was （1.133±0.040） in the psoriatic skin lesions, significantly higher than that in the normal controls （0.744±0.037, P〈0.01）. （2） There were significantly positive correlations between the expression of IL-22/S100A7 mRNA, IL-22/S100A8 mRNA, IL-22/S100A9 mRNA in the psoriasis vulgaris （r1=-0.543, r2=0.774, r3=0.621, P〈0.01）. It was concluded that IL-22 and S 100A7, A8, A9 might play important roles in the occurrence and progression of psoriasis.
基金Supported by National Natural Science Foundation of China,No.81260083Grants from the Guangxi Natural Science Foundation of China,No.2014jj AA40237
文摘AIM:To investigate the effect of interleukin(IL)-22 onhepatic fibrosis in mice and the possible mechanism involved.METHODS:Liver fibrosis was induced in male BALB/c mice by CCl4.Recombinant IL-22(rm IL-22) was administered intraperitoneally in CCl4-treated mice.Fibrosis was assessed by histology and Masson staining.The activation of hepatic stellate cells(HSCs) was investigated by analysis of α-smooth muscle actin expression.The frequencies of T helper(Th) 22 cells,Th17 cells and Th1 cells,the expression of inflammatory cytokines [IL-22,IL-17 A,interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),IL-6,IL-1b] and transcription factors [aryl hydrocarbon receptor(AHR),RAR-related orphan receptor(RORγt),T-bet] m RNA in the liver were investigated.In addition,the plasma levels of IL-22,IL-17 A,IFN-γ,TNF-α,IL-6 and IL-1b were evaluated.RESULTS:Significant elevations in circulating Th22 cells,Th17 cells,Th1 cells,IL-22,IL-17 A,and IFN-γ were observed in the hepatic fibrosis group compared with the control group(P < 0.01).Treatment with rm IL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis,which was confirmed by lower hepatic fibrosis pathological scores(P < 0.01).Rm IL-22 decreased the frequencies of Th22 cells(6.71% ± 0.97% vs 8.09% ± 0.74%,P < 0.01),Th17 cells(4.34% ± 0.37% vs 5.71% ± 0.24%,P < 0.01),Th1 cells(3.09% ± 0.49% vs 4.91% ± 0.73%,P < 0.01),and the levels of IL-22(56.23 ± 3.08 vs 70.29 ± 3.01,P < 0.01),IL-17A(30.74 ± 2.77 vs 45.68 ± 2.71,P < 0.01),and IFN-γ(74.78 ± 2.61 vs 124.89 ± 2.82,P < 0.01).Down-regulation of IL-22,IL-17 A,IFN-γ,TNF-α,IL-6,IL-1b,AHR RORγt,and T-bet gene expression in the liver was observed in the rm IL-22 group(P < 0.01).CONCLUSION:The frequencies of Th22,Th17 andTh1 cells are elevated in hepatic fibrosis.Rm IL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines,thereby ameliorating liver fibrogenesis.
基金supported by the National Natural Science Foundation of China(No. 81360347,No.81260045)
文摘Objective:To observe the effects of interleukin-22(IL-22)on the expression of type Ⅲ collagen,cytokines,growth factors and chemokines in mouse cardiac fibroblasts in vitro.Methods:Mouse cardiac fibroblasts were treated with0μg/L(control),1μg/L(low concentration)and 100μg/L(high concentration)IL-22,respectively.In addition,cells treated with 100μmol/L static(an STAT3 pathway inhibitor)and 100μg/L IL-22 was defined as the block group.After treatment for 48 hours,the mRNA level of collagen type Ⅲ A1(Col3-A1),matrix metalloproteinase-1(Timp-1),IL-22receptor(IL-22R),interleukin 10-related T cellderived inducible factor beta(Iltifb),fibroblast growth factor1(Fgf1)and C-C motif chemokine ligand 4(Ccl4)were determined by RT-PCR.The expression of Col3-A1 in cardiac fibroblasts was also semi-quantified by immunofluorescence.Results:Expression of Col3-A1 decreased in the low and high concentration groups,but significantly increased in the block group(all P <0.05).The expression of Timp-1increased in the low,high concentration and block groups compared with that in the control group,but it was significantly lower in the high concentration group than that in the low concentration group(P <0.05).The expression of IL-22 Rand Iltifb was significantly increased in the low,high concentration and block groups compared with that in the control group(P <0.05),but there was no statistical difference between the high concentration group and block group.The expression of Fgf1 and Ccl4 was significantly decreased in the low,high concentration and block groups compared with that in the control group(P <0.05),but there was no statistic difference between the high concentration group and block group as well.Conclusion:IL-22 effected on the expression of Col3-A1 and Timp-1,which was possibly through the JAK-STAT3 signaling pathway in mice cardiac fibroblasts.
基金supported by the National Natural Science Foundational of China(Key Program),No.U24A20692(to CJZ)the National Natural Science Foundational of China,Nos.82101414(to MLJ),82371355(to CJZ)+4 种基金the National Natural Science Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovation and Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’s Hospital,No.30420230005(to CJZ)Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(to CJZ)。
文摘The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.
基金supported by grants from the National Natural Science Foundation of China(31872746 and 81773620)Scientific Research Projects of Shanghai Municipal Commission of Health and Family Planning(201740140,China)
文摘Diabetic nephropathy(DN)is considered the primary causes of end-stage renal disease(ESRD)and is related to abnormal glycolipid metabolism,hemodynamic abnormalities,oxidative stress and chronic inflammation.Antagonism of vascular endothelial growth factor B(VEGF-B)could effi-ciently ameliorate DN by reducing renal lipotoxicity.However,this pharmacological strategy is far from satisfactory,as it ignores numerous pathogenic factors,including anomalous reactive oxygen species(ROS)generation and inflammatory responses.We found that the upregulation of VEGF-B and downregulation of interleukin-22(IL-22)among DN patients were significantly associated with the progression of DN.Thus,we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS.To meet these challenges,a novel anti-VEGFB/IL22 fusion protein was developed,and its therapeutic effects on DN were further studied.We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction.Moreover,the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity.Collectively,our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN,which highlighted a novel therapeutic approach to DN.
文摘F-652 is a recombinant fusion protein consisting of two human interleukin-22(IL-22)molecules linked to an immunoglobulin constant region(IgG 2-Fc).IL-22 plays critical roles in promoting tissue repair and suppressing bacterial infection.The safety,pharmacokinetics(PK),tolerability,and biomarkers of F-652 were evaluated following a single dose in healthy male volunteers in a randomized,double-blind,placebo-controlled study.Following single-dose subcutaneous(SC)injection of F-652 at 2.0µg/kg into healthy subjects,six out of six subjects experienced delayed injection site reactions,which presented as erythematous and/or discoid eczematous lesions 10 to 17 days post-dosing.F-652 was then administered to the healthy subjects via an intravenous(IV)infusion at 2.0,10,30,and 45µg/kg.No severe adverse event(SAE)was observed during the study.Among the IV-dosed cohorts,eye and skin treatment emergent adverse events(TEAEs)were observed in the 30 and 45µg/kg cohorts.F-652 IV dosing resulted in linear increases in C max and AUC(0–t),and the T 1/2 ranged from 39.4 to 206h in the cohorts.An IV injection of F-652 induced dose-dependent increases in serum marker serum amyloid A,C-reactive protein,and FIB,and decreased serum triglycerides.The serum levels of 36 common pro-inflammatory cytokines/chemokines were not altered by the treatment of F-652 at 45μg/kg.In conclusion,IV administration of F-652 to healthy male volunteers is safe and well-tolerated and demonstrates favorable PK and pharmacodynamic properties.These results warrant further clinical development of F-652 to treat inflammatory diseases.
基金We thank Ms.Brenda Strutt and Jessica Hill for technical help and Dr.Margery Ma from Pfizer,Cambridge,MA for anti-IL-22 antibody.We also thank Dr.Kathleen Hill,Dr.Alexander Timoshenko and Morgan Kleiber for assistance in experimental design and interpretation of the data.This work was supported by grants from the Canadian Institutes of Health Research(CIHR).
文摘Background:In Type 1 diabetes,the insulin-producingβ-cells within the pancreatic islets of Langerhans are destroyed.We showed previously that immunotherapy with Bacillus Calmette-Guerin(BCG)or complete Freund’s adjuvant(CFA)of non-obese diabetic(NOD)mice can prevent disease process and pancreaticβ-cell loss.This was associated with increased islet Regenerating(Reg)genes expression,and elevated IL-22-producing Th17 T-cells in the pancreas.Results:We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas.We therefore quantified the Reg1,Reg2,and Reg3δ(INGAP)mRNA expression in isolated pre-diabetic NOD islets treated with IL-22.We measured IL-22,and IL-22 receptor(R)-αmRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice.Our results showed:1)Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro;2)IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment;3)a reduced expression of IL-22Rαfollowing CFA treatment;4)a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody;and 5)an increased isletβ-cell DNA synthesis in vitro in the presence of IL-22.Conclusions:We conclude that IL-22 may contribute to the regeneration ofβ-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.
