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- Title
IL-6 promotes acute and chronic inflammatory disease in the absence of SOCS3.
- Authors
Croker, Ben A; Kiu, Hiu; Pellegrini, Marc; Toe, Jesse; Preston, Simon; Metcalf, Donald; O'Donnell, Joanne A; Cengia, Louise H; McArthur, Kate; Nicola, Nicos A; Alexander, Warren S; Roberts, Andrew W
- 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.
- Subjects
LYMPHOID tissue; JOINT diseases; ENDOCRINE glands; INTERLEUKIN-6; CELLULAR immunity; AUTOIMMUNE diseases
- Publication
Immunology & Cell Biology, 2012, Vol 90, Issue 1, p124
- ISSN
0818-9641
- Publication type
Article
- DOI
10.1038/icb.2011.29