IL-6 promotes acute and chronic inflammatory disease in the absence of SOCS3

Ben A. Croker, Hiu Kiu, Marc Pellegrini, Jesse Toe, Simon Preston, Donald Metcalf, Joanne A. O'Donnell, Louise H. Cengia, Kate McArthur, Nicos A. Nicola, Warren S. Alexander, Andrew W. Roberts

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31 Citations (Scopus)

Abstract

The lack of expression of the suppressor of cytokine signalling-3 (SOCS3) or inactivation of the negative regulatory capacity of SOCS3 has been well documented in rheumatoid arthritis, viral hepatitis and cancer. The specific qualitative and quantitative consequences of SOCS3 deficiency on interleukin-6 (IL-6 -/-)-mediated pro- and anti-inflammatory responses remain controversial in vitro and unknown in vivo. Mice with a conditional deletion of SOCS3 in hematopoietic cells develop lethal inflammatory disease during adult life and develop gross histopathological changes during experimental arthritis, typified by elevated IL-6 levels. To clarify the nature of the IL-6 responses in vivo, we generated mice deficient in SOCS3 (SOCS3 -/δvav) or both SOCS3 and IL-6 (IL-6 -/-/SOCS3 -/δvav), and examined responses in models of acute and chronic inflammation. Acute responses to IL-1b were lethal to SOCS3 -/δvav mice but not IL-6 -/-/SOCS -/δvav mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1b. Administration of IL-1b to SOCS3 -/δvav mice induced systemic apoptosis of lymphocytes in the thymus, spleen and lymph nodes that was dependent on the presence of IL-6. IL-6 deficiency prolonged survival of SOCS3 -/δvav mice and ameliorated spontaneous inflammatory disease developing during adult life. Infection of SOCS3 -/δvav mice with LCMV induced a lethal inflammatory response that was dependent on IL-6, despite SOCS3 -/δvav mice controlling viral replication. We conclude that SOCS3 is required for survival during inflammatory responses and is a critical regulator of IL-6 in vivo.

Original languageEnglish
Pages (from-to)124-129
Number of pages6
JournalImmunology and Cell Biology
Volume90
Issue number1
DOIs
Publication statusPublished - Jan 2012
Externally publishedYes

Keywords

  • IL-1b
  • IL-6
  • SOCS3
  • suppressor of cytokine signalling-3

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