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

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 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(−/Δ)(vav)) or both SOCS3 and IL-6 (IL-6(−)(/)(−)/SOCS3(−/Δ) (vav)) and examined responses in models of acute and chronic inflammation. Acute responses to IL-1β were lethal to SOCS3(−/Δ) (vav) mice but not IL-6(−)(/)(−)/SOCS3(−/Δ) (vav) mice, indicating that IL-6 was required for the lethal inflammation induced by IL-1β. Administration of IL-1β to SOCS3(−/Δ) (vav) 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(−/Δ) (vav) mice and ameliorated spontaneous inflammatory disease developing during adult life. Infection of SOCS3(−/Δ) (vav) mice with LCMV induced a lethal inflammatory response that was dependent on IL-6, despite SOCS3(−/Δ) (vav) 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.