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IL 6 levels. Croker et al. reported that acute responses to IL 1B were lethal to SOCS3 cKO mice but not SOCS3/IL 6 double KO mice, indicating that loss of SOCS3 is pro inammatory when IL 6 is required for inammation. Furthermore, they showed that infection Aurora B inhibitor of SOCS3 cKO mice with LCMV induced a lethal inammatory response that was dependent on IL 6. Therefore, SOCS3 is probably both pro and anti inammatory depending on the proand anti inammatory action of IL 6. SOCS3 in macrophages may regulate macrophage polarization. At least two distinct subpopulations with different functions, the classically and the alternatively activated macrophages, have been found. Macrophages in which SOCS3 was knocked down by short

in epithelial and lamina propria cells in the colon of mice with intestinal bowel disease, as well as in human ulcerative colitis and Crohns disease patients and in synovial broblasts of RA patients. Forced expression of either SOCS3 or a dominant negative form of STAT3 in mouse arthritis models suppressed the induction/development of the disease, indicating that SOCS3 in non immune cells is probably anti inammatory. These ndings are consistent with the idea that the IL BI-1356 6 and IL 6 related cytokines STAT3 pathway promotes chronic disease progression and SOCS3 is part of this negative feedback loop. This idea is supported by a recent nding that the JAK inhibitor CP 690550 is a potent therapeutic agent for the autoimmune arthritis model by suppressing the IL 6/STAT3 amplication. However, when STAT3 plays a protective role for tissue injury, such as in ConA induced hepatitis, deletion of SOCS3 is anti inammatory. We have recently demonstrated

PARP differentiation of SOCS3 tg T cells was suppressed. The reciprocal regulation of Th1 and Th17 by SOCS1 and SOCS3 is illustrated in Figure 3. In addition, SOCS1 T cells were less responsive to TGF B, although the mechanism has not yet been claried. Reduced STAT3 activation and TGF B signaling may explain the suppression of Th17 differentiation in SOCS1 decient T cells. Our microarray analysis revealed that T bet, Eomesodermin, and G 1 were upregulated in SOCS1deceint T cells under Th17 skewing conditions, all of which have been reported to suppress Th17 differentiation. Role of SOCS1 and SOCS3 in Th differentiation is summarized in Figures