Dataset Information

Role of suppressor of cytokine signaling-1 in murine atherosclerosis.

ABSTRACT:

Background

While the impact of inflammation as the substantial driving force of atherosclerosis has been investigated in detail throughout the years, the influence of negative regulators of pro-atherogenic pathways on plaque development has remained largely unknown. Suppressor of cytokine signaling (SOCS)-1 potently restricts transduction of various inflammatory signals and, thereby modulates T-cell development, macrophage activation and dendritic cell maturation. Its role in atherogenesis, however has not been elucidated so far.

Methods and results

Loss of SOCS-1 in the low-density lipoprotein receptor deficient murine model of atherosclerosis resulted in a complex, systemic and ultimately lethal inflammation with increased generation of Ly-6C(hi) monocytes and activated macrophages. Even short-term exposure of these mice to high-cholesterol dieting caused enhanced atherosclerotic plaque development with accumulation of M1 macrophages, Ly-6C positive cells and neutrophils.

Conclusion

Our data not only imply that SOCS-1 is athero-protective but also emphasize the fundamental, regulatory importance of SOCS-1 in inflammation-prone organisms.

SUBMITTER: Grothusen C

PROVIDER: S-EPMC3531439 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Role of suppressor of cytokine signaling-1 in murine atherosclerosis.

Grothusen Christina C Schuett Harald H Hillmer Anja A Lumpe Stefan S Grote Karsten K Ballmaier Matthias M Bleich Andre A Glage Silke S Tietge Uwe J F UJ Luchtefeld Maren M Schieffer Bernhard B

PloS one 20121227 12

<h4>Background</h4>While the impact of inflammation as the substantial driving force of atherosclerosis has been investigated in detail throughout the years, the influence of negative regulators of pro-atherogenic pathways on plaque development has remained largely unknown. Suppressor of cytokine signaling (SOCS)-1 potently restricts transduction of various inflammatory signals and, thereby modulates T-cell development, macrophage activation and dendritic cell maturation. Its role in atherogenes ...[more]

PMID: 23300554

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Project description:ObjectiveGraves' orbitopathy (GO) is characterized by increased production of proinflammatory cytokines and hyaluronic acid by fibroblasts and their differentiation into adipocytes in response to immunologic stimuli. The suppressor of cytokine signaling-3 (SOCS3) is an inducible negative regulator of the JAK/STAT pathway, implicated in various inflammatory diseases. In this study, we investigated the role of SOCS3 in the inflammatory and adipogenic pathogenesis of GO.MethodsTranscriptome profiling of orbital tissues obtained from five patients with GO who underwent orbital decompression surgery and four healthy subjects was performed using RNA-sequencing. Among the top-ranked differentially expressed genes, we identified 24 hub genes and found SOCS3 to be the most significantly upregulated gene in GO samples compared with that in healthy tissue based on quantitative real-time polymerase chain reaction. SOCS3 expression was analyzed in IL-1β-, and IGF-1-stimulated orbital fibroblasts using quantitative real-time polymerase chain reaction and western blot analysis. Knockdown of SOCS3 using siRNA transfection was performed to assess the effect of SOCS3 on the production of proinflammatory cytokines and adipogenic phenotype.ResultsWe identified 184 consistently differentially expressed genes-120 upregulated and 64 downregulated- in GO tissues compared to the control. SOCS3 mRNA expression was significantly higher in GO tissues (n = 17) compared with that in control (n = 15). IL-1β and IGF-1 enhanced the expression of SOCS3 at mRNA and protein levels. Silencing of SOCS3 suppressed the levels of IL-1β-induced proinflammatory cytokines, including IL-6, IL-8, and ICAM-1. Phosphorylation of NF-kB and Akt was suppressed and adipogenic differentiation was significantly attenuated by SOCS3 knockdown.ConclusionsSOCS3 was remarkably expressed in the adipose tissues of patients with GO and was induced by IL-1β and IGF-1 in orbital fibroblasts. SOCS3 inhibition attenuated the production of proinflammatory cytokines and adipogenesis, suggesting that SOCS3 may be a therapeutic target for controlling the inflammatory and adipogenic mechanisms in GO.

Dataset Information

Role of suppressor of cytokine signaling-1 in murine atherosclerosis.

Background

Methods and results

Conclusion

Publications

Role of suppressor of cytokine signaling-1 in murine atherosclerosis.

Similar Datasets

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