Dysregulated cytokine production by leukocytes, mediated by SOCS1 deficiency, is correlated to skin pathology: implications for therapeutic targeting. (THER6P.851)

Abstract Dysregulated leukocyte activation and cytokine signaling are known to contribute to autoimmunity. Notably, although Suppressor of Cytokine Signaling-1(SOCS1) is important in the regulation of both leukocyte activation and cytokine signaling, how deficiencies in SOCS1 relate to autoimmunity is not well understood. Therefore we analyzed leukocytes from mice bearing heterozygous expression of SOCS1 (SOCS1+/-) for dysregulated immune function. LPS stimulated SOCS1+/- leukocytes exhibited enhanced production of IL6, and IL12. Notably we observed that SOCS1+/-IFNγ-/- mice, but not IFNγ-/-, SOCS1+/-, or wild-type mice exhibited significant skin pathology on the back and ears. The observed skin pathology in SOCS1-/-IFNγ-/- mice was correlated to leukocyte accumulation within draining lymph nodes and spleen. In vitro, SOCS1+/-IFNγ-/- leukocytes activated with αCD3/αCD28 were hyper-proliferative and produced higher levels of IL17 when compared SOCS1+/+ littermates. Finally, a peptide capable of partially mimicking SOCS1 (SOCS1-KIR) was sufficient to reduce excessive proliferation, and aberrant IL12 and IL6 production of SOCS1+/- leukocytes in vitro. Together these results implicate an important role of SOCS1 in the regulation of immune responses. Moreover these results suggest that targeting SOCS1 deficiency, by a mimetic of SOCS1, may have implications in the regulation of skin pathologies mediated by immune dysregulation.