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* Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany;
Life Science Research Unit, University of Luxembourg, Luxembourg;
Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany; and
Department of Biochemistry, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
The recruitment of leukocytes to injured tissue is crucial for the initiation of inflammatory responses as well as for immune surveillance to fight tumor progression. In this study, we show that oncostatin M, a member of the IL-6-type cytokine family and potent proinflammatory cytokine stimulates the expression of the chemokines CCL1, CCL7, and CCL8 in primary human dermal fibroblasts at a faster kinetic than IL-1β or TNF-
. The production of CCL1 and CCL8 is important for migration of monocytes, while specific Abs against CCL1 additionally inhibit the migration of T lymphocytes. We identify the mitogen-activated protein kinases ERK1/2 and p38 as crucial factors for the enhanced expression of CCL1 and CCL8. Depletion of the ERK1/2 target genes c-Jun or c-Fos strongly decrease CCL1 and CCL8 expression, while p38 MAPK prolongs the half-life of CCL1, CCL7, and CCL8 mRNA through inhibition of tristetraprolin. None of the STAT transcription factors STAT1, STAT3, or STAT5 stimulate transcription of CCL1 or CCL8. However, we identify a negative regulatory function of activated STAT5 for the gene expression of CCL1. Importantly, not STAT5 itself, but its target gene cytokine inducible SH2-domain containing protein is required for the STAT5 inhibitory effect on CCL1 expression. Finally, we show that constitutive activation of STAT5 through a mutated form of JAK2 (JAK2 V617F) occurring in patients with myeloproliferative disorders similarly suppresses CCL1 expression. Taken together, we identify novel important inflammatory target genes of OSM which are independent of STAT signaling per se, but depend on MAPK activation and are partly repressed through STAT5-dependent expression of cytokine inducible SH2-domain containing protein.
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 (SFB 542; TP B6 and Forschungszentrum FZ82 to H.M.H. and Tu220/3 to J.T.).
2 Address correspondence and reprint requests to Dr. Heike M. Hermanns, Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, Versbacher Str. 9, Würzburg, Germany. E-mail address: heike.hermanns{at}virchow.uni-wuerzburg.de
3 Abbreviations used in this paper: OSM, oncostatin M; HDF, human dermal fibroblast; MEF, mouse embryonic fibroblast; PEI, polyethylenimine; siRNA, small interfering RNA; TTP, tristetraprolin; CIS, cytokine inducible SH2-domain containing protein.
4 The online version of this article contains supplementary material.
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  F. Entschladen, J. A. Lindquist, E. Serfling, G. Thiel, A. Kieser, K. Giehl, C. Ehrhardt, S. M. Feller, O. Ullrich, F. Schaper, et al. Signal Transduction--Receptors, Mediators, and Genes Sci. Signal., March 24, 2009; 2(63): mr3 - mr3. [Abstract] [Full Text] [PDF]
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