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B Pathway in TLR-Stimulated Human Monocytes and Macrophages1
* Division of Molecular Biotechnology, Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Australia; and
Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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-
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- mRNA or protein production within the first two hours of TLR4 activation. However, SOCS1 suppressed the sustained production of TNF- 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
B. The late effects of LPS are mediated in part through the MyD88-independent pathway activating IRF3 and initiating the production of IFN-β. In response to adenoviral infection and before LPS exposure, monocytes expressed enhanced levels of IFN-β and Myxovirus A mRNA, an anti-viral molecule characterizing IFN-β 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 IFN-β 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Health and Medical Research Council (NHMRC) Grant 275546 (to P.H.H.), a State and Territory Affiliate grant, Arthritis Australia and the Adam Gilchrist Trading Challenge Project grant from Arthritis Australia (to C.M.P.) and NIH CA22556 (to S.E.N.). S.E.N. was supported by an NHMRC Biomedical Career Development Award.
2 Address correspondence and reprint requests to: Dr. Prue Hart, Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, GPO Box 855, West Perth, Australia 6872. E-mail address: prueh{at}ichr.uwa.edu.au
3 Abbreviations used in this paper: Mal, MyD88-adaptor-like; CT, cycle threshold; HEK, human embryonic kidney; IRF, IFN regulatory factor; IB, inhibitory B; MFI, mean fluorescence intensity; MOI, multiplicity of infection; MxA, myxovirus resistance-A; NFB CP, unlabelled NFB probe; mNFB CP, unlabelled mutant NFB probe; SOCS, suppressor of cytokine signaling; TRAM, TRIF-related adaptor molecule; TRIF, toll/interleukin-1 receptor domain-containing adaptor inducing IFN-β; UBE2D2; ubiquitin conjugating enzyme E2D2.
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  A. DiGiandomenico, L. S. Wylezinski, and J. Hawiger Intracellular Delivery of a Cell-Penetrating SOCS1 that Targets IFN-{gamma} Signaling Sci. Signal., July 21, 2009; 2(80): ra37 - ra37. [Abstract] [Full Text] [PDF]
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