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
Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low...Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.展开更多
Background: Coronary heart disease(CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase(MMP)-22 and-29 and pro-inflammatory cytokine interleukin-18(IL18) are present in ...Background: Coronary heart disease(CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase(MMP)-22 and-29 and pro-inflammatory cytokine interleukin-18(IL18) are present in human hearts. IL18 may regulate MMP-22 and-29 expression, which may correlate with CHD progression. Methods and results: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and-29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18(odds ratio(OR)=1.131, P=0.007), MMP-22(OR=1.213, P=0.040), and MMP-29(OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18(coefficient(r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22(r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein(hs-CRP)(r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride(r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22(r=0.845, P<0.001) and MMP-29(r=0.548, P<0.001). Conclusions: Our observations suggest that IL18, MMP-22 and-29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and-29 levels in these patients.展开更多
AIM:To evaluate the proinflammatory effects and molecular mechanisms of interleukin(IL)-17 in intestinal epithelial cell line HT-29.METHODS:HT-29 cells were cultured with IL-17,tumor necrosis factor(TNF)-α,or the com...AIM:To evaluate the proinflammatory effects and molecular mechanisms of interleukin(IL)-17 in intestinal epithelial cell line HT-29.METHODS:HT-29 cells were cultured with IL-17,tumor necrosis factor(TNF)-α,or the combination of both IL-17 and TNF-α.Real-time PCR and Western blot were used to measure the gene expression levels of neutrophil chemokines CXCL1,CXCL2,CXCL5,CXCL6,IL-8and TH-17 cell chemokine CCL20,the phosphorylation levels of p38 and TNF-α,and the expression level of IL-8,after using the p38 inhibitor in HT-29 cells.The stable Act1 knockdown HT-29 cell line was established to further test the phosphorylation changes of p38,after using IL-17 and TNF-α.RESULTS:After HT-29 cells were cultured with IL-17and TNF-α,the expression levels of neutrophil chemokines(CXCL1,CXCL2,CXCL5,CXCL6,IL-8)and Th17chemokine(CCL20)significantly improved(24.96±2.53,28.47±2.87,38.08±2.72,33.47±2.41,31.7±2.38,44.37±2.73,respectively),and the differences were all statistically significant(P<0.01).Western blot results showed that IL-17 obviously enhanced the phosphorylation level of p38,which was induced by TNF-α.Compared with the control group,the expression level of IL-8 significantly declined(9.47±1.36 vs 3.06±0.67,P<0.01)when TH-29 cells were cultured with IL-17and TNF-α.p38 inhibition assay showed that the p38pathway played an essential role in the inflammatory response induced by IL-17.p38 phosphorylation levels could not be changed after using IL-17 and TNF-αin the stable Act1 knockdown HT-29 cell line.CONCLUSION:IL-17 significantly promoted the gene expression levels of TNF-α-induced neutrophil chemokines and Th17 cell chemokine.It is obvious that IL-17and TNF-αhave synergistic effects on p38.展开更多
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 China International Medical Foundation(Z-2019-42-1908-4)Natural Science Basic Research Program of Shaanxi Province(2019JM-440).
文摘Objective:To investigate the antifibrotic effects of curcumin in a transverse aortic constriction(TAC)mouse model and elucidate its molecular mechanisms.Methods:Male C57BL/6 mice underwent TAC and received vehicle,low-dose curcumin(50 mg/kg),high-dose curcumin(200 mg/kg),high-dose curcumin plus a scrambled control antagomir,or high-dose curcumin plus anti-miR-29b treatments.Cardiac function was assessed by echocardiography.Fibrosis was evaluated by histology,collagen volume fraction,and hydroxyproline content.Expression of miR-29b,HDAC4,and fibrosis-related markers(Col1a1,Col3a1,TGF-β1)was measured by quantitative RT-PCR and Western blotting assays.Myocardial procollagen type I carboxy-terminal propeptide was determined by ELISA,and HDAC4-specific enzymatic activity was assayed using a fluorogenic kit.Results:Curcumin improved cardiac function,reduced fibrosis,restored miR-29b expression,and suppressed HDAC4 expression and activity in a dose-dependent manner.Furthermore,curcumin decreased myocardial procollagen type I carboxy-terminal propeptide levels,confirming reduced collagen synthesis.Anti-miR-29b administration partially abrogated the antifibrotic and cardioprotective effects of curcumin.Conclusions:Curcumin attenuates pressure overload-induced cardiac fibrosis and dysfunction in a TAC mouse model via modulation of the miR-29b/HDAC4 axis and suppression of collagen synthesis.
基金supported by the University of Science and Technology Innovation Team of Henan(No.14IRTSTHN018)the Science and Technology Talents Team Construction Program of Zhengzhou City Science and Technology Talents(No.131PLJRC670),Chinathe National Institutes of Health(Nos.HL60942 and HL123568),USA
文摘Background: Coronary heart disease(CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase(MMP)-22 and-29 and pro-inflammatory cytokine interleukin-18(IL18) are present in human hearts. IL18 may regulate MMP-22 and-29 expression, which may correlate with CHD progression. Methods and results: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and-29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18(odds ratio(OR)=1.131, P=0.007), MMP-22(OR=1.213, P=0.040), and MMP-29(OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18(coefficient(r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22(r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein(hs-CRP)(r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride(r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22(r=0.845, P<0.001) and MMP-29(r=0.548, P<0.001). Conclusions: Our observations suggest that IL18, MMP-22 and-29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and-29 levels in these patients.
基金Supported by Minhang District Natural Science Foundation(to Wang YL)the Science and Technology Commission in Shanghai,No.10411968500 National Natural Science Foundation of China,No.81001324
文摘AIM:To evaluate the proinflammatory effects and molecular mechanisms of interleukin(IL)-17 in intestinal epithelial cell line HT-29.METHODS:HT-29 cells were cultured with IL-17,tumor necrosis factor(TNF)-α,or the combination of both IL-17 and TNF-α.Real-time PCR and Western blot were used to measure the gene expression levels of neutrophil chemokines CXCL1,CXCL2,CXCL5,CXCL6,IL-8and TH-17 cell chemokine CCL20,the phosphorylation levels of p38 and TNF-α,and the expression level of IL-8,after using the p38 inhibitor in HT-29 cells.The stable Act1 knockdown HT-29 cell line was established to further test the phosphorylation changes of p38,after using IL-17 and TNF-α.RESULTS:After HT-29 cells were cultured with IL-17and TNF-α,the expression levels of neutrophil chemokines(CXCL1,CXCL2,CXCL5,CXCL6,IL-8)and Th17chemokine(CCL20)significantly improved(24.96±2.53,28.47±2.87,38.08±2.72,33.47±2.41,31.7±2.38,44.37±2.73,respectively),and the differences were all statistically significant(P<0.01).Western blot results showed that IL-17 obviously enhanced the phosphorylation level of p38,which was induced by TNF-α.Compared with the control group,the expression level of IL-8 significantly declined(9.47±1.36 vs 3.06±0.67,P<0.01)when TH-29 cells were cultured with IL-17and TNF-α.p38 inhibition assay showed that the p38pathway played an essential role in the inflammatory response induced by IL-17.p38 phosphorylation levels could not be changed after using IL-17 and TNF-αin the stable Act1 knockdown HT-29 cell line.CONCLUSION:IL-17 significantly promoted the gene expression levels of TNF-α-induced neutrophil chemokines and Th17 cell chemokine.It is obvious that IL-17and TNF-αhave synergistic effects on p38.
