PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity

Liu, Bin; Mink, Sheldon; Wong, Kelly A.; Stein, Natalie; Getman, Crescent; Dempsey, Paul W.; Wu, Hong; Shuai, Ke

doi:10.1038/ni1104

Cited by 230 publications

(216 citation statements)

References 43 publications

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“…Herein, we show that CXCL10 induction is regulated at the transcriptional level. Although the CXCL10 gene represents a classical example of a gene that responds to type I/type II IFN-in a STAT1-dependent fashion [24,25], our results show that, in neutrophils, its induction does not reflect a synergistic enhancement of STAT1 activation by IFN-c and LPS. Furthermore, we previously showed that there is no evidence for any IRF-3 or ATF-2/c-Jun involvement regulating CXCL10 mRNA expression in IFN-c plus LPS-treated neutrophils [11], consistent with the data excluding endogenous IFN-b as an intermediate regulating CXCL10 induction.…”

Section: Discussioncontrasting

confidence: 53%

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

et al. 2007

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The CXCL10 chemokine is a critical chemoattractant for the recruitment of activated Th1 and NK cells into inflammatory sites. CXCL10 is typically produced by myeloid cells in response to IFN-c, as well as by neutrophils, though the latter require a costimulation with IFN-c and LPS. In this study, we investigated the molecular mechanism(s) whereby IFN-c and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By primary transcript real-time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFN-c combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFN-c-induced STAT1 activation and the lipopolysaccharide (LPS)-induced NF-jB activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFN-c or LPS in monocytes. Finally, pharmacological inhibitors of NF-jB demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-c in neutrophils, and by LPS or IFN-c in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-c toward CXCL10 gene expression likely reflects the cooperative induction of the NF-jB and STAT1 transcription factors by LPS and IFN-c, respectively. IntroductionCXCL10/IFN-c-inducible protein 10 (IP-10) is a critical component of several immune responses, acting notably as a chemoattractant for activated NK and Th1 cells into sites of inflammation. CXCL10 mediates its various activities by binding to CXCR3 expressed on activated Th1 and NK cells [1], and influences the behavior of nonimmune cells that express a CXCR3. For instance, it inhibits endothelial cell proliferation through interfering with the function of receptors for the growth factors, basic fibroblast growth factor and vascular endothelial growth factor, resulting in the inhibition of angiogenesis [2].Neutrophils are cells of the innate immune system that play an essential role in antimicrobial defense via the release of numerous toxic mediators [3]. In addition, extensive research has now clearly established that the release of chemokines and cytokines constitutes yet another key contribution of neutrophils to innate immunity (reviewed in reference [4]). Among the chemokines produced by neutrophils both in vitro and in vivo, CXCL10 stands out as being somewhat peculiar in terms of its induction characteristics, as originally shown by us [5,6] as well as by other groups [7][8][9]. Indeed, CXCL10 expression occurs in vitro only if However, the molecular bases of the particular inducibility of CXCL10 in human neutrophils have only been partially elucidated thus far. In this regard, we have recently clarified that the reason explaining the inability of LPS to induce CXCL10 mRNA expression in neutrophils reflects the fact that in this cell type, LPS is unable to mobilize the intracellular MyD88-independent pathway upon TLR4 binding [11]. As a result, LPS fails to...

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Section: Discussioncontrasting

confidence: 53%

Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN‐γ in human neutrophils

et al. 2007

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“…Interestingly, an increased binding of STAT1 to the promoters of PIAS1-sensitive genes, but not PIAS1-insensitive genes, in PIAS1-deficient macrophages was observed [36]. These results suggest that the specificity of PIAS1 on STAT1-mediated gene regulation may be determined, at least in part, by the promoter microenvironment of STAT1-target genes.…”

Section: Pias In the Regulation Of Stat Signalingmentioning

confidence: 80%

“…Pias1 -/-mice are produced at a frequency 50% lower than the expected Mendelian ratio due to partial perinatal lethality. The surviving PIAS1-deficient mice are runted compared with their wild-type littermates [36]. Wild type and Pias1 -/-bone-marrow-derived macrophages (BMDMs) and primary mouse embryonic fibroblasts (MEFs) have been used to analyze the physiological role of PIAS1 in STAT1 signaling [36].…”

Section: Pias In the Regulation Of Stat Signalingmentioning

confidence: 99%

“…The surviving PIAS1-deficient mice are runted compared with their wild-type littermates [36]. Wild type and Pias1 -/-bone-marrow-derived macrophages (BMDMs) and primary mouse embryonic fibroblasts (MEFs) have been used to analyze the physiological role of PIAS1 in STAT1 signaling [36]. Quantitative PCR analysis indicates that the removal of PIAS1 leads to the increased transcriptional activation of STAT1-dependent genes in response to IFN-β or IFN-γ stimulation.…”

Section: Pias In the Regulation Of Stat Signalingmentioning

confidence: 99%

“…Most interestingly, gene expression profiling studies showed that PIAS1-deficiency affects the expression of only a subset of IFN-stimulated genes (PIAS1-sensitive genes). For example, the transcription of GBP1 (guanylate binding protein), MIG (monokine induced by IFN-gamma) and IP10 (IFN-gamma-inducible protein 10 kDa) in responding to IFN-γ was enhanced by 2-5 fold in Pias1 null cells as compared to that in wild type cells, while the transcription of IRF1 (interferon regulatory factor-1), NOS2 (nitric-oxide synthase 2) or SOCS1 was not altered [36]. Thus, unlike other general negative regulators of JAK-STAT signaling pathways, PIAS1 does not inhibit the entire IFN-responsive genes.…”

Section: Pias In the Regulation Of Stat Signalingmentioning

confidence: 99%

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Regulation of cytokine signaling pathways by PIAS proteins

2006

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Cytokines activate multiple signal transduction pathways to regulate gene expression. STATs and NF-kB are two important families of transcription factors activated by cytokines. Abnormal regulation of STAT and NF-kB activities has been associated with human diseases. The protein inhibitor of activated STAT (PIAS) protein family has been proposed to interact with over 60 proteins, many of which are transcription factors involved in the immune system. PIAS proteins regulate transcription through several mechanisms, including blocking the DNA-binding activity of transcription factors, recruiting transcriptional co-repressors and promoting protein sumoylation. This article is to review the role of PIAS proteins in the regulation of STAT and NF-kB signaling pathways.

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