RAPID COMMUNICATION Stem Cell Factor-Induced Migration of Mast Cells Requires p38 Mitogen-Activated Protein Kinase Activity 1 Magnus Sundstro ¨m, Jessica Alfredsson, Niclas Olsson, and Gunnar Nilsson 2 Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden Stem cell factor (SCF) can be considered a cardinal cytokine in mast cell biology as it affects mast cell differentiation, survival, and migration. The objective of this study was to investigate the role of two mito- gen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) and p38, in SCF-in- duced cell migration. This was examined in mouse mast cells by using PD 098059 and SB203580, which are specific inhibitors of mitogen-induced extracellular kinase (MEK) and p38 MAP kinase, respectively. SCF induced a rapid and transient activation of ERK and p38 in a dose-dependent manner. Inhibition of p38 activity by SB203580 was paralleled with a marked reduction of migration toward SCF, whereas the effect of the MEK inhibitor was less pronounced. This is the first report of a physiological function of SCF-depen- dent activation of p38. Whether p38-mediated mast cell migration is a possible target for suppression of mast cell hyperplasia remains to be determined. © 2001 Academic Press Key Words: chemotaxis; mast cells; mitogen-acti- vated protein kinase; inflammation; p38. INTRODUCTION Mast cells are inflammatory cells of hematopoietic origin. These cells have been shown to be multifunc- tional as they can contribute to both innate and specific immunity [1]. Mast cells are tissue based and function as effector cells in the allergic response, mediating the inflammation underlying the immediate-type hyper- sensitivity. Accumulation of mast cells has been de- scribed in several inflammatory conditions, e.g., aller- gic rhinitis [2], asthma [3], and rheumatoid arthritis [4]. Mast cells are believed to contribute to both the development and the severity of the above-mentioned disorders by synthesis and release of potent inflamma- tory mediators (reviewed in [5]). The increase in mast cell number can be due to proliferation of resident mast cells, recruitment and maturation of mast cell precur- sors, or migration of mature mast cells from the sur- rounding tissues. Several recent reports provide sup- port for the hypothesis that growth factor- and chemokine-mediated chemotaxis of mast cells within tissues can be an important mechanism for the rapid increase of mast cell number at sites of inflammation [6 –13]. Stem cell factor (SCF) is a crucial growth factor in mast cell biology. It regulates such diverse cellular functions as proliferation, differentiation, survival, ad- hesion, and release of inflammatory mediators [14 – 22]. SCF also acts as a mast cell chemotaxin [8, 9]. Furthermore, injection of SCF into the skin causes mast cell hyperplasia [23, 24], indicating that SCF may be of importance for the recruitment of mast cells in vivo. The pathways involved in transducing signals lead- ing to SCF-induced mobilization of cells are not fully understood. SCF acts by binding to the Kit receptor [25], a member of the class III receptor tyrosine kinase family [26]. Binding of SCF to the extracellular part of Kit activates different intracellular signaling compo- nents, including the three members of the mitogen- activated protein (MAP) kinase family: Jun N-terminal kinase, p38, and extracellular signal-regulated kinase (ERK) [27–30]. The MAP kinase/ERK cascade is im- portant in transmitting signals that preferentially lead to cell proliferation and differentiation; however, the role of ERK as a regulator of migration is poorly un- derstood. The p38 signaling pathway can be activated by a variety of extracellular stimuli such as growth factors, cytokines, and cellular stress. Functional consequences of p38 activity are a direct or indirect activation of transcription factors. This leads to regulation of proin- 1 This work was supported by grants from the Swedish Cancer Society, Ollie and Elof Ericssons Foundation, King Gustaf V’s 80 Years Foundation, Selanders Foundation, Go ¨ran Gustavssons Foun- dation, and Hans von Kantzow’s Foundation. 2 To whom reprint requests should be addressed. Fax: +46 18 558931. E-mail: Gunnar.Nilsson@genpat.uu.se. 144 0014-4827/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved. Experimental Cell Research 267, 144 –151 (2001) doi:10.1006/excr.2001.5239, available online at http://www.idealibrary.com on