Alternative Activation of STAT1 and STAT3 in Response to Interferon-γ

Qing, Yulan; Stark, George R.

doi:10.1074/jbc.m406413200

Cited by 288 publications

(309 citation statements)

References 67 publications

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“…Consequently, STAT1 activation by IFN-b can be assumed to inhibit OPN production. Meanwhile, STAT1 activation can reciprocally reduce STAT3 activation, which is responsible for transcription of IL-17 [47]. Although how the signaling events interacting each other to depress the transcription of OPN and IL-17 still needs to be explored, this finding complements the IFN-b/DC/Th17 theory by showing direct regulation of OPN and IL-17 production in CD4 1 T cells.…”

Section: Discussionmentioning

confidence: 72%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

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IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is Ã These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

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Section: Discussionmentioning

confidence: 72%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

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“…However, it is also possible that the observed effect is due to a different STAT that is activated in the course of LPS response only in the absence of STAT-1. Several recent reports have demonstrated that this is a realistic scenario [30,31].…”

Section: Discussionmentioning

confidence: 90%

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

et al. 2006

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There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level; however, there has been limited progress integrating this information to understand how biological systems function in vivo. For example, the anti‐inflammatory cytokine IL‐10 is thought to down‐regulate the effects of the pro‐inflammatory cytokine IFN‐γ on monocyte activation following LPS stimulation. However, the often‐postulated reciprocal regulation of IL‐10 gene expression by IFN‐γ has not been studied in vivo. Here we demonstrate that the regulation of IL‐10 gene expression has at least two phases following challenge with LPS or a gram‐negative organism. In C57BL/6 mice, early IL‐10 induction occurs independently of STAT‐1, while a delayed active repression of IL‐10 gene expression is critically dependent on STAT‐1, but only partially dependent upon IFN‐α/β and IFN‐γ. This in vivo IL‐10 production comes from blood monocytes, but not tissue macrophages, and cannot be reproduced in vitro. This study provides new insights into the regulation of IL‐10 following challenge with a gram‐negative organism, and highlights the importance of studying these cytokine regulatory pathways in vivo.

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“…Interleukin 6, though not the dominant inducer of STAT1, can contribute to STAT1 activation (Qing and Stark, 2004). We assessed secretion of the IL6 protein after treatment of HeLa cells with DMA or BrdU þ DMA by immunoblotting ( Figure 3a) and cytometric To discriminate the specific contribution of BrdU versus DMA to IL6 gene expression (Figure 3d), we followed the dynamics of IL6 mRNA after exposure of HeLa cells to either BrdU or DMA.…”

Section: Stat1-activating Ligands Ifnb and Il6 Are Secreted By Senescmentioning

confidence: 99%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

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Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2 0 -deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon c (IFNc), IFNb and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/ chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNb-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

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Alternative Activation of STAT1 and STAT3 in Response to Interferon-γ

Cited by 288 publications

References 67 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

Cytokine expression and signaling in drug-induced cellular senescence

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Alternative Activation of STAT1 and STAT3 in Response to Interferon-γ

Cited by 288 publications

References 67 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

Cytokine expression and signaling in drug-induced cellular senescence

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Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS