Activation of STAT3 by IL-6 and IL-10 in Primary Human Macrophages Is Differentially Modulated by Suppressor of Cytokine Signaling 3

130

124

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.

Section: Discussionsupporting

confidence: 78%

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

Herrero

et al. 2003

130

124

“…Thus, it is possible that the PGE 2 -induced inhibition of IL-6 signaling might be due to de novo synthesis of SOCS3. In our studies, IL-10-induced STAT3 phosphorylation was not affected by PGE 2 -mediated induction of SOCS3, which is consistent with another report suggesting that IL-10-induced STAT3 activation is much less sensitive to the inhibitory activity of SOCS3 (25).…”

Section: Modulation Of Cytokine-induced Stat3 Phosphorylation Is Depesupporting

confidence: 80%

“…Because SOCS3 is a major feedback inhibitor of IL-6-induced STAT signaling (20,24,25), we suspected that SOCS3 may be involved in the PGE 2 -mediated inhibition of IL-6-induced STAT3 activation. PGE 2 rapidly induced SOCS3 mRNA expression within 30 min (Fig.…”

Section: Modulation Of Cytokine-induced Stat3 Phosphorylation Is Depementioning

confidence: 99%

Prostaglandin E2 Augments IL-10 Signaling and Function

Cheon

Rho

Choi

et al. 2006

In inflamed joints of rheumatoid arthritis, PGE2 is highly expressed, and IL-10 and IL-6 are also abundant. PGE2 is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE2 on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE2 significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE2 suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE2-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE2-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE2 selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE2 may modulate immune responses by alteration of cytokine signaling in THP-1 cells.

“…Support for this concept comes from STAT3 DNA binding studies performed in the presence of proinflammatory stimuli. These studies found that the initial STAT3 activated by the IL-6R in the presence of TLR4 or IL-1R signaling caused a block in DNA binding activity of STAT3 that was not observed when STAT3 was activated by the IL-10R (42)(43)(44). Therefore, it is possible that STAT3 located in the environment of gp130 is subject to additional modifications that inhibit STAT3 function.…”

Section: Different Types Of Stat3 Signalsmentioning

confidence: 99%

General Nature of the STAT3-Activated Anti-Inflammatory Response

Kasmi

Holst²,

Coffre

et al. 2006

202

179

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.