Suppressor of Cytokine Signaling 1 Inhibits Cytokine Induction of CD40 Expression in Macrophages

Wesemann, Duane R.; Dong, Yongchun; O'Keefe, George M; Nguyen, Vince T.; Benveniste, Etty N.

doi:10.4049/jimmunol.169.5.2354

Cited by 60 publications

(61 citation statements)

References 58 publications

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“…In contrast, targeted expression of SOCS-1 in oligodendrocytes protects them against the injurious effects of IFN-␥ (63). Our findings in macrophages/microglia indicate that both SOCS-1 and SOCS-3 attenuate inflammatory events in these cells (35,45,64). Thus, depending on the CNS cell type, SOCS-3 expression exerts beneficial or detrimental effects.…”

Section: Discussionmentioning

confidence: 72%

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

Qin¹,

Roberts²,

Niyongere³

et al. 2007

The Journal of Immunology

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155

145

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Immunological activation of macrophages/microglia within the CNS leads to the production of cytokines and chemokines that ultimately impact on glial and neuronal function. Suppressor of cytokine signaling (SOCS) proteins are negative regulators of adaptive and innate immune responses. Our previous studies demonstrated that SOCS-3 attenuates macrophage/microglial activation in vitro, suggesting that SOCS-3 may exert beneficial effects for immune-mediated CNS diseases in vivo. In this study, we describe LPS as a potent inducer of SOCS-3 transcription and expression in macrophages/microglia. An analysis of the SOCS-3 promoter indicates that AP-1 and IFN-γ activation sequence (GAS) elements are involved in LPS-induced SOCS-3 transcription. LPS-induced SOCS-3 expression was diminished in IL-10-deficient macrophages at later time points, indicating the involvement of endogenous IL-10 in this response. Blocking STAT-3 expression and activation using STAT-3 small interfering RNA reduced LPS-induced SOCS-3 gene expression. LPS activated the MAPK-ERK1/2, JNK, and p38 pathways that, in addition to STAT-3, were also involved in LPS-induced SOCS-3 expression. LPS treatment of cells led to the acetylation of histones H3 and H4 on the SOCS-3 promoter and the recruitment of STAT-3, c-Jun, c-Fos, CREB-binding protein, p300, and RNA polymerase II to the endogenous SOCS-3 promoter in a time-dependent manner. These results indicate that LPS-induced MAPK activation, the production of endogenous IL-10, and STAT-3 activation play critical roles in SOCS-3 expression, which provides for feedback attenuation of cytokine-induced immune and inflammatory responses in macrophages and microglia.

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Section: Discussionmentioning

confidence: 72%

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

Qin¹,

Roberts²,

Niyongere³

et al. 2007

The Journal of Immunology

Self Cite

155

145

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“…In the RAW264.7 macrophage cell line, IFN-␥ and TNF-␣ synergize in the activation of NF-B (14,15). In these cells, IFN-␥ synergizes with endogenously produced TNF-␣ to give stronger and more prolonged NF-B activation than does exogenous TNF-␣ treatment or IFN-␥ treatment alone (achieved by the use of a neutralizing anti-TNF-␣ Ab to inhibit signaling by endogenously produced TNF-␣) (14,15).…”

Section: Stat-1␣ and Ifn-␥ As Modulators Of Tnf-␣ Signaling Inmentioning

confidence: 99%

“…In these cells, IFN-␥ synergizes with endogenously produced TNF-␣ to give stronger and more prolonged NF-B activation than does exogenous TNF-␣ treatment or IFN-␥ treatment alone (achieved by the use of a neutralizing anti-TNF-␣ Ab to inhibit signaling by endogenously produced TNF-␣) (14,15). These results prompted us to search for mechanisms by which these two signaling pathways could communicate to enhance NF-B activation.…”

Section: Stat-1␣ and Ifn-␥ As Modulators Of Tnf-␣ Signaling Inmentioning

confidence: 99%

STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex

Wesemann

Benveniste

2003

The Journal of Immunology

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TNF-α and IFN-γ cooperate in the activation of macrophages. TNF-α-dependent activation of NF-κB is stronger in the presence of IFN-γ. STAT-1α associates with TNFR1 in TNF-α-treated cells, and this association attenuates TNF-α-mediated NF-κB activation. We hypothesized that nuclear localization of STAT-1α due to IFN-γ signaling would preclude it from being recruited to the TNFR1 and therefore enhance TNF-α-induced NF-κB activation. In the RAW264.7 macrophage cell line, TNF-α treatment indeed recruits STAT-1α to the TNFR1, and this association is abrogated when cells are exposed to IFN-γ. TNF-α treatment induces a more robust activation of NF-κB in STAT-1α-deficient cells, and restoration of STAT-1α inhibits TNF-α-dependent NF-κB activation. Our results suggest that a receptor-proximal level of cross-talk exists between these two cytokine pathways: IFN-γ limits STAT-1α availability to the TNFR1 by depleting STAT-1α from the cytoplasm, thus allowing for optimal NF-κB activation upon TNF-α ligation.

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“…Its signaling activity results in the upregulation of pro-inflammatory adhesion molecules (ICAM1, VCAM1, E-selectin and P-selectin) and cytokines and chemokines (IL-1, IL-6, IL-8, IL-12, TNF-alpha and MIP-1alpha) and has been implicated in the pathogenesis of several CNS disorders (71,72). Wesemann et al (70) showed that overexpression of SOCS1 inhibits CD40 expression by preventing STAT1 phosphorylation, suppressing TNF-alpha secretion and the subsequent NF-kappaB activity in macrophages stimulated by IFN-gamma (70).…”

Section: Ppar-gamma-independent-mechanismsmentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

379

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Suppressor of Cytokine Signaling 1 Inhibits Cytokine Induction of CD40 Expression in Macrophages

Cited by 60 publications

References 58 publications

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia

STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

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