SOCS1 Regulates the IFN but Not NF kappa B Pathway in TLR-Stimulated Human Monocytes and Macrophages
- Author(s)
- Prele, CM; Woodward, EA; Bisley, J; Keith-Magee, A; Nicholson, SE; Hart, PH;
- Details
- Publication Year 2008-12-01,Volume 181,Issue #11,Page 8018-8026
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- Abstract
- SOCS1 can regulate TLR-mediated signal transduction, yet mechanistic studies in murine macrophages have been confusing and contradictory. This study has used an adenoviral transfection system to determine the role of SOCS1 in the regulation of TNF-alpha production by activated human monocytes. Monocytes were infected with AdV-SOCS1 or with an empty vector control, AdV-GFP, for 24 h before activation with the TLR4 ligand, LPS. SOCS1 did not regulate TNF-a mRNA or protein production within the first two hours of TLR4 activation. However, SOCS1 suppressed the sustained production of TNF-a by primary human monocytes and synovial fluid macrophages ex vivo. In addition, SOCS1 regulated the production of IL-6, but not IL-10, by monocytes. Analysis of the early signaling pathway downstream of TLR4 demonstrated that SOCS1 had no regulatory effect on the activation or on the DNA binding capacity of NF kappa B. The late effects of LPS are mediated in part through the MyD88-independent pathway activating IRF3 and initiating the production of IFN-beta. In response to adenoviral infection and before LPS exposure, monocytes expressed enhanced levels of IFN-beta and Myxovirus A mRNA, an anti-viral molecule characterizing IFN-beta activity. These two genes were reduced in AdV-SOCS1-infected cells. Further, SOCS1 regulated IFN-dependent pathways in LPS-activated cells as evidenced by reduced TFN-beta production and STAT1 phosphorylation. Using AdV-infection to dissect SOCS1 control of IFN-dependent pathways, this study suggests that SOCS1-regulation of the IFN-dependent component of the LPS-induced TLR4 signaling pathway may contribute to the down-regulation of inflammatory cytokine production by AdV-SOCS1-infected human monocytes. The Journal of Immunology, 2008, 181: 8018-8026.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- TOLL-LIKE RECEPTORS; INNATE ANTIVIRAL RESPONSE; FACTOR-ALPHA PRODUCTION; CYTOKINE SIGNALING-1; IMMUNE-RESPONSE; DENDRITIC CELLS; ANTITUMOR IMMUNITY; STAT1 ACTIVATION; CPG-DNA; SUPPRESSOR
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Creation Date: 2008-12-01 12:00:00