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

Immunol Cell Biol. 2012 Jan;90(1):124-9. doi: 10.1038/icb.2011.29. Epub 2011 Apr 26.

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-1β were lethal to SOCS3(-/Δvav) mice but not IL-6(-/-)/SOCS3(-/Δvav) mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1β. Administration of IL-1β 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chronic Disease
  • Cytokines / immunology
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / pharmacology
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / immunology*
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / deficiency
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / immunology*
  • Survival Analysis

Substances

  • Cytokines
  • Interleukin-1beta
  • Interleukin-6
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins