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Published online before print February 14, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0705418

Received for publication July 28, 2005.
Revised December 19, 2005.
Accepted for publication December 23, 2005.

Article

Conditional up-regulation of IL-2 production by p38 MAPK inactivation is mediated by increased Erk1/2 activity

Olga Kogkopoulou ^*, Evaggelos Tzakos ^*, George Mavrothalassitis , Cosima T. Baldari , Fotini Paliogianni , Howard A. Young ^¶, and George Thyphronitis ^*||@

*Department of Pathophysiology, School of Medicine, University of Athens, Greece; School of Medicine, University of Crete and IMBB-FORTH, Voutes, Heraklion, Greece; Department of Evolutionary Biology, University of Siena, Italy, Department of Microbiology, School of Medicine, University of Patras, Greece; ^¶Laboratory of Experimental Immunology, Center for Cancer Research, NCI-Frederick, Maryland; and ^||UPR CNRS 9045, Institut André Lwoff, Villejuif, France

^@ To whom correspondence should be addressed. E-mail: gthyfron{at}vjf.cnrs.fr.

	Abstract

The p38 mitogen-activated protein kinase regulates many cellular processes in almost all eukaryotic cell types. In T cells, p38 was shown to regulate thymic development and cytokine production. Here, the role of p38 on interleukin-2 (IL-2) production by human peripheral blood CD4⁺ T cells was examined. When T cells were stimulated under weak stimulation conditions, pharmaceutical and molecular p38 inhibitors induced a dramatic increase of IL-2 production. In contrast, IL-2 levels were not affected significantly when strong stimulation was provided to T cells. The increase in IL-2 production, following p38 inhibition, was associated with a strong up-regulation of extracellular signal-regulated kinase (Erk)1/2 activity, and the Erk inhibitor U0126 was able to counteract the effect of p38 inhibition on IL-2 production further, supporting the conclusion that p38 mediates its effect through Erk. Thus, our results suggest that the p38 kinase, through its ability to control Erk activation levels, acts as a gatekeeper, which prevents inappropriate IL-2 production. Also, the finding that p38 acts in a strength-of-stimulation-dependent way provides an explanation for previously reported, contradictory results regarding the role of this kinase in IL-2 expression.

Key Words: T lymphocytes • protein kinases • transcription factors • signal transduction

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