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Regulation of Suppressor of Cytokine Signaling 3 (SOCS3) mRNA Stability by TNF- Involves Activation of the MKK6/p38^MAPK/MK2 Cascade¹

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^* and Johannes G. Bode^2,*

^* Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University, Düsseldorf, Germany; Department of Biochemistry, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Aachen, Germany; Department of Molecular Virology, University of Münster, Münster, Germany; Laboratory of Neurobiology and the ^¶ Office of Clinical Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and ^|| Department of Biochemistry, Medical School Hannover, Hannover, Germany

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-. In contrast to IL-6, TNF- increases SOCS3 expression by stabilizing SOCS3 mRNA. Activation of the MAPK kinase 6 (MKK6)/p38^MAPK-cascade is required for TNF--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--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-. In summary, these data indicate that TNF- 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.

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 the Deutsche Forschungsgemeinschaft (Bonn, Germany), through the Sonderforschungsbereich 575 "Experimentelle Hepatologie" and by the Bennigsen-Foerder Preis.

² Address correspondence and reprint requests to Dr. Johannes G. Bode, Department of Gastroenterology, Hepatology, and Infectiology, Heinrich-Heine University, Moorenstrasse 5, Düsseldorf, Germany. E-mail address: Johannes.Bode{at}t-online.de

³ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; ARE, adenosine/uridine-rich element; CT, delta cycle threshold; DIG, digoxygenin; Epo, erythropoietin; HA, hemagglutinin; MEF, mouse embryonic fibroblast; MK2, MAPK-activated protein kinase 2; MKK6, MAPK kinase 6; SDHA, succinate dehydrogenase; SH2, Src homology 2; siRNA, small interfering RNA; TTP, tristetraprolin; Tet, tetracycline; UTR, untranslated region.

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