IRAK-Dependent Phosphorylation of Stat1 on Serine 727 in Response to Interleukin-1 and Effects on Gene Expression

Abstract

Interleukin-1 (IL-1) induces the phosphorylation of Stat1 on serine 727 but not on tyrosine 701. Analyses of mutant I1A cells, which lack the IL-1 receptor-associated kinase (IRAK), and of I1A cells reconstituted with deletion mutants of IRAK show that the IL-1-mediated phosphorylation of Stat1 on serine requires the IRAK protein but not its kinase activity and does not involve phosphatidylinositol-3'-kinase (PI3K) or the mitogen-activated protein (MAP) kinases p38 or ERK. IRAK and Stat1 interact in vivo, and this interaction is increased in response to IL-1, suggesting that IRAK may serve to recruit the as yet unknown IL-1-induced Stat1 serine kinase. Chemical inhibitors or dominant-negative forms of signaling components required to activate NF-kappa B, ATF, or AP-1 in response to IL-1 do not affect the phosphorylation of Stat1 on serine. IL-1 and tumor necrosis factor (TNF) enhance the serine phosphorylation of Stat1 that occurs in response to interferon-gamma (IFN-gamma) and potentiate IFN-gamma-mediated, Stat1-driven gene expression, thus contributing to the synergistic activities of these proinflammatory cytokines.

Dual Function of Interleukin-1β for the Regulation of Interleukin-6-induced Suppressor of Cytokine Signaling 3 Expression

“…5). We confirmed the results of Nguyen et al (30) and additionally excluded a requirement of NF-B for STAT1 serine phosphorylation, suggesting that enhanced SOCS3 expression is not a result of STAT1 serine phosphorylation. The necessity of NF-B for the enhancing effect of IL-1␤ on SOCS3 induction and the computer-aided identification of two putative NF-B binding regions within the SOCS3 promoter led us to look for NF-B binding in this promoter area in vivo (Fig.…”

“…Serine phosphorylation of both transcription factors has been shown to affect transcriptional of activity (36,37). Recently, Stark and collaborators described STAT1 serine phosphorylation in response to IL-1␤ (30). In respect to this study and the knowledge that NF-B activation is crucial for the enhancing effect of IL-1␤ on IL-6-induced SOCS3 expression, we asked whether IL-1␤-induced serine phosphorylation of STAT1 is also dependent on NF-B (Fig.…”

Inhibitor of κB kinase is required to activate a subset of interferon γ-stimulated genes

“…Phosphorylation of serine-727 of Stat1 in response to IL-1 or TNF, as well as the ability of IFNs to increase the transactivation function of p65NF B, indicate that the signaling components of these two pathways interact in complex and intricate ways (33,34,38). We demonstrated previously that the phosphatidylinositol 3-kinase (PI3K)͞AKT pathway plays an important role in activating the IKK complex to phosphorylate p65NF B, helping to activate NF-B-dependent gene transcription in response to IL-1 or TNF (49).…”

Critical role of all - trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions

“…We then investigated the expression and activation of the downstream signal molecules for IL-1R and IL-6R. It has been well recognized that IL-1 and/or IL-6 exert their effects through the activation of STAT1 and STAT3, respectively (29)(30)(31). We hypothesized that the addition of atRA might reduce STAT1 and STAT3 activation following IL-1 and IL-6 stimulation.…”