Overactivation of inflammatory signaling in keratinocytes is critical for psoriatic skin inflammation,but its regulatory mechanisms remain incompletely understood.Here,we demonstrate that the cytokine CSBF inhibits bo...Overactivation of inflammatory signaling in keratinocytes is critical for psoriatic skin inflammation,but its regulatory mechanisms remain incompletely understood.Here,we demonstrate that the cytokine CSBF inhibits both individual and synergistic proinflammatory signaling induced by IL-17A and TNF-α(IL-17A/TNF-α)in keratinocytes,playing a protective role in psoriatic inflammation.The expression of CSBF was increased in the skin lesions and serum of psoriatic patients,and IL-17A/TNF-αenhanced its production.Csbf deletion exacerbated IMQ-induced psoriasis-like skin inflammation and led to hyperactivation of IL-17A/TNF-αsignaling in keratinocytes.The CSBF protein significantly ameliorated psoriatic manifestations and suppressed IL-17A/TNF-αsignaling through the receptor SUSD2.Mechanistically,CSBF-SUSD2 competed with TRAF6 and TNFR1 for interaction with ACT1,inhibiting the IL-17A/TNF-αsignaling pathway.Overall,the anti-inflammatory cytokine CSBF has the potential to be a therapeutic option for psoriasis by targeting keratinocytes.展开更多
IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects...IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 A.Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts.The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic Cytochrome-c.After narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal microscopy.IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing.Moreover,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis.This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.展开更多
TH17 inflammatory helper cells constitute an important subset of T lymphocytes that secrete the cytokine interleukin 17(IL-17)and thereby drive inflammation in response to microbial antigens.Dysregulation of TH17 cell...TH17 inflammatory helper cells constitute an important subset of T lymphocytes that secrete the cytokine interleukin 17(IL-17)and thereby drive inflammation in response to microbial antigens.Dysregulation of TH17 cells,characterized by increased IL-17 production,is a hallmark of many inflammatory and autoimmune diseases such as asthma,multiple sclerosis and rheumatoid arthritis.1 The adaptor molecule and E3 ubiquitin ligase Act1 is a key signaling molecule downstream of the IL-17 receptor(IL-17R)that triggers activation of the NF-kB and mitogen-activated protein kinase(MAPK)signaling pathways,which in turn coordinate the induction of cytokine and chemokine genes that are central to the inflammatory response.2 However,the details of IL-17 signaling and precisely how Act1 is regulated have been poorly understood.In a recent issue of Nature Immunology,Bulek et al.have identified the kinase I kappa B kinase i(IKKi,also known as IKKe)as a critical regulator of Act1 and IL-17 signaling.展开更多
基金supported by grants from the Beijing Municipal Natural Science Foundation(No.7232095)the National Natural Science Foundation of China(Nos.82171750,82150104,82203938,82030095,and 82071850).
文摘Overactivation of inflammatory signaling in keratinocytes is critical for psoriatic skin inflammation,but its regulatory mechanisms remain incompletely understood.Here,we demonstrate that the cytokine CSBF inhibits both individual and synergistic proinflammatory signaling induced by IL-17A and TNF-α(IL-17A/TNF-α)in keratinocytes,playing a protective role in psoriatic inflammation.The expression of CSBF was increased in the skin lesions and serum of psoriatic patients,and IL-17A/TNF-αenhanced its production.Csbf deletion exacerbated IMQ-induced psoriasis-like skin inflammation and led to hyperactivation of IL-17A/TNF-αsignaling in keratinocytes.The CSBF protein significantly ameliorated psoriatic manifestations and suppressed IL-17A/TNF-αsignaling through the receptor SUSD2.Mechanistically,CSBF-SUSD2 competed with TRAF6 and TNFR1 for interaction with ACT1,inhibiting the IL-17A/TNF-αsignaling pathway.Overall,the anti-inflammatory cytokine CSBF has the potential to be a therapeutic option for psoriasis by targeting keratinocytes.
基金the Shenzhen Science and Technology Plan(No.JCYJ20220530142009021)the National Natural Science Foundation of China(No.82060678,82060851,81760674)the Nanshan District of Shenzhen Science and Technology Project(China)(No.2019057).
文摘IL-17 A is a promoter of colorectal cancer initiation and progression.Narciclasine is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor actions.The effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 A.Narciclasine reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine xenografts.The results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic Cytochrome-c.After narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal microscopy.IL17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A silencing.Moreover,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor prognosis.This study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.
文摘TH17 inflammatory helper cells constitute an important subset of T lymphocytes that secrete the cytokine interleukin 17(IL-17)and thereby drive inflammation in response to microbial antigens.Dysregulation of TH17 cells,characterized by increased IL-17 production,is a hallmark of many inflammatory and autoimmune diseases such as asthma,multiple sclerosis and rheumatoid arthritis.1 The adaptor molecule and E3 ubiquitin ligase Act1 is a key signaling molecule downstream of the IL-17 receptor(IL-17R)that triggers activation of the NF-kB and mitogen-activated protein kinase(MAPK)signaling pathways,which in turn coordinate the induction of cytokine and chemokine genes that are central to the inflammatory response.2 However,the details of IL-17 signaling and precisely how Act1 is regulated have been poorly understood.In a recent issue of Nature Immunology,Bulek et al.have identified the kinase I kappa B kinase i(IKKi,also known as IKKe)as a critical regulator of Act1 and IL-17 signaling.
