Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been w...Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been well described.In this study,we report that thousand and one kinase 1(TAOK1)functions as a negative regulator of IL-17-mediated signal transduction and inflammation.TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB.We further demonstrate that TAOK1 interacts with IL-17 receptor A(IL-17RA)independent of its kinase activity,and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1(nuclear factor activator 1,also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2)complex.Consistent with this,TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid-induced experimental model of inflammatory bowel disease,likely by its promotion of the IL-17-mediated signaling pathway.TAOK1 expression is decreased in the colons of ulcerative colitis patients.In conclusion,these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.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
基金supported by grants from the National Key Research and Development Program of China(2016YFA0502201)the National Natural Science Foundation of China(81571550,81671613)+2 种基金the Natural Science Foundation of Zhejiang Province(LY18H100001,LY15H100001)the‘Double First-rate’project initiatives,the Shanghai Key Laboratory of Cell Engineering(14DZ2272300)the Shanghai Leading Academic Discipline Project(B905).
文摘Interleukin 17(IL-17)is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases.However,the regulation of its signaling transduction has not been well described.In this study,we report that thousand and one kinase 1(TAOK1)functions as a negative regulator of IL-17-mediated signal transduction and inflammation.TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB.We further demonstrate that TAOK1 interacts with IL-17 receptor A(IL-17RA)independent of its kinase activity,and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1(nuclear factor activator 1,also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2)complex.Consistent with this,TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid-induced experimental model of inflammatory bowel disease,likely by its promotion of the IL-17-mediated signaling pathway.TAOK1 expression is decreased in the colons of ulcerative colitis patients.In conclusion,these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.
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.
