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Mechanisms of SOCSI regulation of TNF production by primary human monocytes

Prêle, C., Woodward, E.A. and Hart, P.H. (2007) Mechanisms of SOCSI regulation of TNF production by primary human monocytes. Inflammation Research, 56 (S3). S372.

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Enhanced SOCS1 expression following exposure of murine macrophages to LPS implicated SOCS1 in the control of LPS-mediated signaling. SOCS1 regulates NFkB signaling in murine macrophages, blocking at the level of Mal or IkBa phosphorylation. We investigated the role of SOCS1 in regulating the production TNF by LPS and Pam3CSK4-activated primary human monocytes. Blood monocytes were isolated by centrifugal elutriation and either infected with an adenoviral vector expressing SOCS1 (AdV-SOCS1), control vector (AdVGFP) or left untreated. AdV-SOCS1 monocytes were exposed to TLR4 and TLR2 ligands, LPS (500 ng/ml) or Pam3CSK4 (300 ng/ml). FACS analysis demonstrated infection efficiencies of 50_4% and 67_4% (n=16, mean _ SEM) of monocytes expressing AdV-GFP or AdVSOCS1 at MOI 50. AdV-SOCS1 blocked LPS and Pam3CSK4 induced TNF mRNA and protein production in a dose-dependent manner. In contrast, IL-6 and IL-10 production by AdV-SOCS1-infected monocytes was not blocked. AdV-SOCS1 also blocked LPS and Pam3CSK4- induced TNF production by macrophages isolated from synovial fluid. Infection efficiencies of 67_1% or 72_1% were obtained. Quantitative Western blot analysis revealed that the classically defined NFkB pathway was not altered at the level of IkBa or p65 activation. Furthermore, the kinetics of LPS and Pam3CSK4- induced IkBa phosphorylation and degradation in AdVSOCS1 monocytes remained unaffected (n=5 and 2 donors, respectively). Further, analysis of parallel MAPK pathways demonstrated no block in p38 or ERK MAPK pathways. These data suggest that SOCS1 regulation of LPS and Pam3CSK4-induced TNF production by human monocytes occurs downstream of TLRs, possibly at the level of transcription.

Item Type: Journal Article
Publisher: Springer
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