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JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1¹

Dilip Kumar^*, Judith Hosse^*,, Christine von Toerne^*, Elfriede Noessner and Peter J. Nelson^2,*

^* Medizinische Poliklinik, Ludwig-Maximilians-University of Munich, Munich, Germany; and Helmholtz Center, Munich, Institute of Molecular Immunology, Munich, Germany

The MAPKs ERK, JNK, and p38 control diverse aspects of the immune response, including regulation of cytotoxin biology in NK cells and CTL. The chemokine CCL5 is coreleased with the cytotoxins, perforin, the granzymes, and granulysin, during the lethal hit administered by cytotoxic CD8⁺ T cells (CTL). CCL5 expression is up-regulated relatively late in CTL coincident with their functional maturation 3–7 days after activation. Unlike T cells, NK cells have the ability to kill virally infected or transformed cells when directly isolated from the peripheral circulation. In this study, we show that in contrast to T cells, peripheral blood NK cells express CCL5 constitutively. The use of specific inhibitors of the JNK, ERK, and p38 MAPK pathways showed that the JNK pathway controls expression of CCL5 by NK cells. Promoter-reporter assays identified a compact region of the CCL5 promoter responsible for the constitutive transcription of CCL5 by NK cells. EMSA, chromatin immune precipitation, the use of heterologous promoters, and site-directed mutagenesis demonstrated that transcription in NK cells is largely controlled through binding of the transcription factor specificity protein 1 to a region –75 to –56 upstream of the site of transcriptional initiation. Specificity protein 1 expression, and in turn the constitutive expression of CCL5, was found to be controlled through constitutive activation of the JNK/MAPK pathway in peripheral blood NK cells.

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 grants from the Deutsche Forschungsgemeinschaft (SFB 571 C2 to P.J.N., and SFB-TR36 B6 and A7 to P.J.N. and E.N., respectively), the European Union (Network of Excellence "MAIN" FP6-502935 to P.J.N.), and P6 "INNOCHEM" (to P.J.N.).

² Address correspondence and reprint requests to Dr. Peter J. Nelson, Medizinische Poliklinik, Ludwig-Maximilians-Universität München, Schillerstrasse 42, 80336, Munich, Germany. E-mail address: peter.nelson{at}med.uni-muenchen.de

³ Abbreviations used in this paper: KLF13, Krüppel-like factor 13; Act D, actinomycin D; ChiP, chromatin immunoprecipitation; CHX, cycloheximide; DAPI, 4',6'-diamidino-2-phenylindole; MFI, median fluorescence intensity; PKC, protein kinase C; qRT-PCR, quantitative RT-PCR; 5' UTR, 5' untranslated region.

⁴ The online version of this article contains supplementary material.