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Dysregulation of the inflammatory response can lead to diseases such as rheumatoid arthritis, Crohn’s disease, or septic shock. The cytokine IL-10 plays a role in limiting the magnitude, duration, and detrimental outcome of the in-flammatory response (Moore et al., 2001). This was shown both with the generation of IL-10– deficient mice that spontaneously develop in-flammatory bowel disease (Kühn et al., 1993) and with the identification of patients with homo-zygous mutations in the IL-10 receptor subunits who present with early-onset colitis (Glocker et al., 2009). IL-10 is produced by numerous cells in-cluding Th1, Th2, Th17, T reg, CD8+ T cells, B cells, and myeloid cells (Saraiva and O’Garra, 2010). One of IL-10’s key functions is the regu-lation of pathogen-mediated activation of mac-rophages and dendritic cells. It inhibits the T cell–activating potential of APC by down-regulating MHC class II and the expression of costimulatory molecules such as CD80 and CD86 (Buelens et al., 1995). IL-10 also inhibits the expression of chemokines, inflammatory enzymes, and potent proinflammatory cyto-kines such as TNF, the target for multiple clini-cal strategies in rheumatoid arthritis and Crohn’s disease (Feldmann and Maini, 2003). Although recent advances have lead to a greater understanding of the regulation of IL-10 production (Saraiva and O’Garra, 2010), the precise mechanism of IL-10–dependent inhibi-tion of TNF is less clear. Activation of STAT3, as a consequence of IL-10 binding to its cell surface receptor (IL-10R1/IL-10R2), is critical for mediating the antiinflammatory respons