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 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.