General Nature of the STAT3-Activated Anti-Inflammatory Response

Abstract

Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

“…The results of this article appear to be consistent with the mechanism by which IL-10 induces anti-inflammatory responses through STAT3 in macrophages (21,49,50), but not with the present results. This discrepancy might result from the differences in the Cre promoter used for generation of STAT3-deficient mice, Tie2 vs Lck promoters.…”

“…Therefore, the STAT3 activated by IL-10 is considered to differ from STAT3 activated by IL-6 (21,49,50). The only obvious distinction between these receptor types is that the IL-6R is regulated by SOCS3, whereas the other anti-inflammatory STAT3-activating receptors, IL-10R, is not (49).…”

“…These results may presumably imply a role of STAT3 in IL-27-induced cell proliferation. In addition, because one of the IL-27R subunits is the common gp130, and IL-27 can activate STAT3 and induce the suppressor of cytokine signaling (SOCS)-3 expression (19,20), the possibility that IL-27 induces anti-inflammatory response in a mechanism similar to the IL-10-induced STAT3-mediated one was discussed previously (21,22). However, the precise role of STAT3 and its molecular mechanism in not only IL-27-induced cell proliferation but also IL-27-induced anti-inflammatory response remain to be elucidated.…”

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…pSTAT3, which has antagonistic effect on pSTAT1 (27,28), plays a key role in suppressing the function of neutrophils, NK cells, DCs (31)(32)(33) and negatively regulating the Th1-mediated inflammatory response (30,31). Therefore, the balance of pSTAT1 and pSTAT3 plays an important role in regulating immune response and maintaining immunohomeostasis.…”

“…Activation of STAT1 promotes the activation of dentritic cells (DCs) (22,23) and natural killer (NK) cells (24), and inhibits the development of regulatory T cells (25,26). pSTAT3, which has antagonistic effect on pSTAT1 (27,28), is not only a potent negative regulator of the Th1-mediated inflammatory response, but also an activator of many genes that are crucial for immune regulation (29,30). Down-regulation of STAT3 could enhance Th1 type immune response and activate DCs, NK cells and macrophages (31)(32)(33).…”