HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Fehrenbach, K. Articles by Huber, M. PubMed PubMed Citation Articles by Fehrenbach, K. Articles by Huber, M.

Steel Factor Enhances Supraoptimal Antigen-Induced IL-6 Production from Mast Cells via Activation of Protein Kinase C-β¹

Kerstin Fehrenbach^2,*, Eva Lessmann^2,*, Carolin N. Zorn^*, Marcel Kuhny^*, Gordon Grochowy^*, Gerald Krystal, Michael Leitges and Michael Huber^3,*,,¶

^* Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, and Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway; and ^¶ Rheinisch-Westfälische Technische Hochschule Aachen University, Medical Faculty, Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, Aachen, Germany

Ag-triggered mast cell (MC) activation follows a bell-shaped dose-response curve. Reduced activation in response to supraoptimal Ag concentrations is thought to be due to preferential engagement of inhibitory-acting proteins like SHIP1, Lyn, and protein kinase C (PKC)-. We show in this study that short-term prestimulation with Steel factor (SF) prevents supraoptimal Ag inhibition, resulting in synergistic MC degranulation and IL-6 secretion. These events are preceded by synergistic phosphorylation/activation of numerous signaling proteins, e.g., Erk, p38, and LAT. However, these effects of prestimulation with SF appear not to be due to reduced engagement of the attenuator SHIP1. Pharmacological analyses suggest that the activation of conventional PKCs is important for this synergy. Specifically, although we found that the conventional PKC inhibitor, Gö6976, likely has some PKC-independent targets in MCs, it led us to further studies that established SF plus Ag-induced IL-6 secretion was severely impaired in PKC-β^–/– MCs, but not PKC-^–/– MCs. Thus, PKC-β joins PI3K and Btk as important players in this synergistic MC activation.

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 Grant Hu794/4-2 from the Deutsche Forschungsgemeinschaft.

² K.F. and E.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Michael Huber, Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, University Hospital, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail address: mhuber{at}ukaachen.de

⁴ Abbreviations used in this paper: MC, mast cell; BMMC, bone marrow-derived MC; PKC, protein kinase C; PKB, protein kinase B; SF, Steel factor; PLC, phospholipase C; LAT, linker for activated T cell; NTAL, non-T cell activation linker; WT, wild type.