Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6
Influenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mech...
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doaj-56470274ca7e4e44ae2b0928d5621c2a2020-11-24T21:27:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-08-011010.3389/fimmu.2019.01843469735Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6Shasha Liu0Shasha Liu1Ruoxiang Yan2Biao Chen3Biao Chen4Qidong Pan5Yuhai Chen6Jinxuan Hong7Lianfeng Zhang8Wenjun Liu9Song Wang10Ji-Long Chen11CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaCollege of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaCollege of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaCollege of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, ChinaInstitute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Beijing, ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, ChinaCollege of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, ChinaCollege of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou, ChinaInfluenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mechanisms underlying such a response are poorly understood. Here we found from both in vivo and in vitro studies that IAV not only induced a surge of IL-6 release, but also greatly upregulated expression of suppressor of cytokine signaling-3 (SOCS3), the potent suppressor of IL-6-associated signal transducer and activator of transcription 3 (STAT3) signaling. Interestingly, there existed a cytokine-independent mechanism of the robust induction of SOCS3 by IAV at early stages of the infection. Furthermore, we employed SOCS3-knockdown transgenic mice (TG), and surprisingly observed from virus challenge experiments using these mice that disruption of SOCS3 expression provided significant protection against IAV infection, as evidenced by attenuated acute lung injury, a higher survival rate of infected animals and lower viral load in infected tissues as compared with those of wild-type littermates under the same condition. The activity of nuclear factor-kappa B (NFκB) and the expression of its target gene IL-6 were suppressed in SOCS3-knockdown A549 cells and the TG mice after infection with IAV. Moreover, we defined that enhanced STAT3 activity caused by SOCS3 silencing was important for the regulation of NFκB and IL-6. These findings establish a critical role for IL-6-STAT3-SOCS3 axis in the pathogenesis of IAV and suggest that influenza virus may have evolved a strategy to circumvent IL-6/STAT3-mediated immune response through upregulating SOCS3.https://www.frontiersin.org/article/10.3389/fimmu.2019.01843/fullimmune responseSOCS3IL-6inflammationinfluenza virus |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shasha Liu Shasha Liu Ruoxiang Yan Biao Chen Biao Chen Qidong Pan Yuhai Chen Jinxuan Hong Lianfeng Zhang Wenjun Liu Song Wang Ji-Long Chen |
spellingShingle |
Shasha Liu Shasha Liu Ruoxiang Yan Biao Chen Biao Chen Qidong Pan Yuhai Chen Jinxuan Hong Lianfeng Zhang Wenjun Liu Song Wang Ji-Long Chen Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 Frontiers in Immunology immune response SOCS3 IL-6 inflammation influenza virus |
author_facet |
Shasha Liu Shasha Liu Ruoxiang Yan Biao Chen Biao Chen Qidong Pan Yuhai Chen Jinxuan Hong Lianfeng Zhang Wenjun Liu Song Wang Ji-Long Chen |
author_sort |
Shasha Liu |
title |
Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 |
title_short |
Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 |
title_full |
Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 |
title_fullStr |
Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 |
title_full_unstemmed |
Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6 |
title_sort |
influenza virus-induced robust expression of socs3 contributes to excessive production of il-6 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-08-01 |
description |
Influenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mechanisms underlying such a response are poorly understood. Here we found from both in vivo and in vitro studies that IAV not only induced a surge of IL-6 release, but also greatly upregulated expression of suppressor of cytokine signaling-3 (SOCS3), the potent suppressor of IL-6-associated signal transducer and activator of transcription 3 (STAT3) signaling. Interestingly, there existed a cytokine-independent mechanism of the robust induction of SOCS3 by IAV at early stages of the infection. Furthermore, we employed SOCS3-knockdown transgenic mice (TG), and surprisingly observed from virus challenge experiments using these mice that disruption of SOCS3 expression provided significant protection against IAV infection, as evidenced by attenuated acute lung injury, a higher survival rate of infected animals and lower viral load in infected tissues as compared with those of wild-type littermates under the same condition. The activity of nuclear factor-kappa B (NFκB) and the expression of its target gene IL-6 were suppressed in SOCS3-knockdown A549 cells and the TG mice after infection with IAV. Moreover, we defined that enhanced STAT3 activity caused by SOCS3 silencing was important for the regulation of NFκB and IL-6. These findings establish a critical role for IL-6-STAT3-SOCS3 axis in the pathogenesis of IAV and suggest that influenza virus may have evolved a strategy to circumvent IL-6/STAT3-mediated immune response through upregulating SOCS3. |
topic |
immune response SOCS3 IL-6 inflammation influenza virus |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.01843/full |
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