Background Human interleukin(IL)-37 is a constituent of the IL-1 family with potent anti-inflammatory and immunosuppressive attributes.It has been demonstrated extensive beneficial effects on various diseases;however,...Background Human interleukin(IL)-37 is a constituent of the IL-1 family with potent anti-inflammatory and immunosuppressive attributes.It has been demonstrated extensive beneficial effects on various diseases;however,its role in the pathogenesis of diabetic cardiomyopathy(DCM)remains unclear.Methods In vivo,DCM mouse model was established with streptozotocin injection and a high-fat diet in WT and cardiac fibroblasts(CFs)specific hIL-37b overexpression mice(IL-37-Tg).In vitro,primary mouse CFs were isolated from the hearts of adult mice and cultured with high levels of glucose and palmitic acid.Cardiac function of the mice was assessed using echocardiography.Masson staining,immunofluorescence,western blot and RT-PCR assays were employed to evaluate the expression of cardiac fibrosis and SOCS3-JAK2-STAT3 signaling pathway-related proteins.Results In this study,we found that CFs specific IL-37-Tg significantly ameliorated cardiac dysfunction and reduced collagen production by inhibiting the JAK2-STAT3 axis,as evidenced by the decreased levels of p-JAK2 and p-STAT3 in the heart of CFs specific IL-37-Tg DCM mice.The beneficial effects of IL-37 were consistently observed in CFs treated with high glucose(HG)and palmitic acid(PA).Moreover,we also discovered that the presence of IL-37 increased the expression of SOCS3,a crucial regulator of JAK/STAT signaling,in DCM mice and HG and PA-treated CFs.Finally,the anti-fibrotic action of IL-37 in HG and PAtreated CFs was abolished when either SOCS3 was genetically knocked down or JAK2/STAT3 was pharmacologically activated.Conclusions Our findings indicate that IL-37 exerts its antifibrotic effect by promoting SOCS3-mediated JAK2-STAT3 inactivation and may be considered as a potential therapeutic agent for DCM.展开更多
基金funded by the National Natural Science Foundation of China(No.81800330)Natural Science Foundation of Shanghai(No.22ZR1414700)Shanghai Pujiang Program(No.21P1401400).
文摘Background Human interleukin(IL)-37 is a constituent of the IL-1 family with potent anti-inflammatory and immunosuppressive attributes.It has been demonstrated extensive beneficial effects on various diseases;however,its role in the pathogenesis of diabetic cardiomyopathy(DCM)remains unclear.Methods In vivo,DCM mouse model was established with streptozotocin injection and a high-fat diet in WT and cardiac fibroblasts(CFs)specific hIL-37b overexpression mice(IL-37-Tg).In vitro,primary mouse CFs were isolated from the hearts of adult mice and cultured with high levels of glucose and palmitic acid.Cardiac function of the mice was assessed using echocardiography.Masson staining,immunofluorescence,western blot and RT-PCR assays were employed to evaluate the expression of cardiac fibrosis and SOCS3-JAK2-STAT3 signaling pathway-related proteins.Results In this study,we found that CFs specific IL-37-Tg significantly ameliorated cardiac dysfunction and reduced collagen production by inhibiting the JAK2-STAT3 axis,as evidenced by the decreased levels of p-JAK2 and p-STAT3 in the heart of CFs specific IL-37-Tg DCM mice.The beneficial effects of IL-37 were consistently observed in CFs treated with high glucose(HG)and palmitic acid(PA).Moreover,we also discovered that the presence of IL-37 increased the expression of SOCS3,a crucial regulator of JAK/STAT signaling,in DCM mice and HG and PA-treated CFs.Finally,the anti-fibrotic action of IL-37 in HG and PAtreated CFs was abolished when either SOCS3 was genetically knocked down or JAK2/STAT3 was pharmacologically activated.Conclusions Our findings indicate that IL-37 exerts its antifibrotic effect by promoting SOCS3-mediated JAK2-STAT3 inactivation and may be considered as a potential therapeutic agent for DCM.
