Document Detail

Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-alpha involves activation of the MKK6/p38MAPK/MK2 cascade.
MedLine Citation:
PMID:  17312125     Owner:  NLM     Status:  MEDLINE    
The potential of some proinflammatory mediators to inhibit gp130-dependent STAT3 activation by enhancing suppressor of cytokine signaling (SOCS) 3 expression represents an important molecular mechanism admitting the modulation of the cellular response toward gp130-mediated signals. Thus, it is necessary to understand the mechanisms involved in the regulation of SOCS3 expression by proinflammatory mediators. In this study, we investigate SOCS3 expression initiated by the proinflammatory cytokine TNF-alpha. In contrast to IL-6, TNF-alpha increases SOCS3 expression by stabilizing SOCS3 mRNA. Activation of the MAPK kinase 6 (MKK6)/p38(MAPK)-cascade is required for TNF-alpha-mediated stabilization of SOCS3 mRNA and results in enhanced SOCS3 protein expression. In fibroblasts or macrophages deficient for MAPK-activated protein kinase 2 (MK2), a downstream target of the MKK6/p38(MAPK) cascade, basal SOCS3-expression is strongly reduced and TNF-alpha-induced SOCS3-mRNA stabilization is impaired, indicating that MK2 is crucial for the control of SOCS3 expression by p38(MAPK)-dependent signals. As a target for SOCS3 mRNA stability-regulating signals, a region containing three copies of a pentameric AUUUA motif in close proximity to a U-rich region located between positions 2422 and 2541 of the 3' untranslated region of SOCS3 is identified. One factor that could target this region is the zinc finger protein tristetraprolin (TTP), which is shown to be capable of destabilizing SOCS3 mRNA via this region. However, data from TTP-deficient cells suggest that TTP does not play an irreplaceable role in the regulation of SOCS3 mRNA stability by TNF-alpha. In summary, these data indicate that TNF-alpha regulates SOCS3 expression on the level of mRNA stability via activation of the MKK6/p38(MAPK) cascade and that the activation of MK2, a downstream target of p38(MAPK), is important for the regulation of SOCS3 expression.
Christian Ehlting; Wi S Lai; Fred Schaper; Erwin D Brenndörfer; Raphaela-Jessica Matthes; Peter C Heinrich; Stephan Ludwig; Perry J Blackshear; Matthias Gaestel; Dieter Häussinger; Johannes G Bode
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  178     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-21     Completed Date:  2007-04-24     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2813-26     Citation Subset:  AIM; IM    
Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University, Moorenstrasse 5, Düsseldorf, Germany.
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MeSH Terms
3T3 Cells
Gene Expression Regulation / drug effects,  physiology*
Intracellular Signaling Peptides and Proteins
MAP Kinase Kinase 6 / immunology,  metabolism
MAP Kinase Signaling System / drug effects,  physiology*
Macrophages / enzymology,  immunology
Protein Kinases / immunology,  metabolism
Protein-Serine-Threonine Kinases
RNA Stability / drug effects,  physiology*
RNA, Messenger / biosynthesis*,  immunology
Suppressor of Cytokine Signaling Proteins / biosynthesis*,  immunology
Tristetraprolin / immunology,  metabolism
Tumor Necrosis Factor-alpha / immunology*,  pharmacology
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/RNA, Messenger; 0/Socs3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/Tristetraprolin; 0/Tumor Necrosis Factor-alpha; EC 2.7.-/Protein Kinases; EC 2.7.1.-/MAP-kinase-activated kinase 2; EC 2.7.1.-/Map2k6 protein, mouse; EC Kinases; EC Kinase Kinase 6

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