Reprogramming of IL-10 Activity and Signaling by IFN-γ

Abstract

One important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-γ, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-γ inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-γ broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-γ induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-γ switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-γ. These results demonstrate that IFN-γ operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.

IFN-γ-Primed Macrophages Exhibit Increased CCR2-Dependent Migration and Altered IFN-γ Responses Mediated by Stat1

“…It has been long appreciated that Stat1 and Stat3 have opposing biological functions, and evidence is emerging that these two transcription factors antagonize each other's action in cytokine signal transduction pathways (9,28,38,39). Our results further support the notion that Stat1 suppresses the activation of gene expression mediated by Stat3-dependent pathways (schematically illustrated in Fig.…”

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

“…Analysis of these data, kindly provided by Drs. This mechanism, which operates within hours, may be different from what occurs when cells are primed for 1 or 2 days before adding a stimulus (Hu et al, 2006) (Herrero et al, 2003). When using a system with a 2day priming period then this will alter the entire gene expression program of a cell with many indirect effects (Herrero et al, 2003).…”

IL-27 Activates Human Monocytes via STAT1 and Suppresses IL-10 Production but the Inflammatory Functions of IL-27 Are Abrogated by TLRs and p38

“…For example, proinflammatory IFN-␥ activates predominantly STAT1 (31) while the potent anti-inflammatory IL-10 activates predominantly STAT3 (22,32). More pleiotropic cytokines, such as IL-6 and IFN-␣, activate both STAT1 and STAT3 (33,34) and we have shown that conditions that augment STAT1 activation, such as priming macrophages (Ms) 3 with IFN-␥, increase the proinflammatory properties of cytokines and can even confer activating functions to 26,35). IL-27 activates both STAT1 and STAT3 in myeloid cells and thus has the potential to induce both proinflammatory and anti-inflammatory effects.…”