Prolonged and excessive inflammation is implicated in resistance to the biological actions of IGF-I and contributes to the pathophysiology of neurodegenerative, metabolic and muscle-wasting disorders. IL-10 is a critical anti-inflammatory cytokine that restrains inflammatory responses in macrophages and T cells by inhibiting cytokine and chemokine synthesis and reducing expression of their receptors. Here we demonstrate that IL-10 plays a protective role in non-hematopoietic cells by suppressing the ability of exogenous IL-1 to inhibit IGF-I-induced myogenin and myosin heavy chain expression in myoblasts. This action of IL-10 is not caused by impairing IL-1-induced synthesis of IL-6 or the ability of IL-1 to activate two members of the MAPK family, ERK1/2 or p38. Instead, this newly-defined protective role of IL-10 occurs by specifically reversing IL-1 activation of the JNK kinase pathway. IL-10 blocks IL-1-induced phosphorylation of JNK, but not ERK1/2 or p38, indicating that only the JNK component of IL-1-induced MAPK signaling pathway is targeted by IL-10. This conclusion is supported by the finding that a specific JNK inhibitor acts similarly to IL-10 to restore IGF-I-induced myogenin expression, which is suppressed by IL-1. Collectively, these data demonstrate that IL-10 acts in a novel, non-classical, protective manner in non-hematopoietic cells to inhibit the IL-1 receptor-induced JNK kinase pathway, resulting in prevention of IGF-I resistance.