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Studies of conditional SOCS3-deficient mice have shown that SOCS3 deficiency, but not SOCS1 deficiency, results in sustained activation of STAT3 in response to IL-6 [8,41]. The analysis of SOCS3-deficient macrophages has indicated that SOCS3 is a crucial inhibitor of the IL-6-induced transcriptional response [42]. However, SOCS3 is dispensable for both the negative feedback inhibition and the immunoregulatory action of IL-10 in macrophages [41]. On the contrary, SOCS1 was found to directly inhibit IL-10-mediated signaling [43]. 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