Combined Stimulation with the T Helper Cell Type 2 Cytokines Interleukin (IL)-4 and IL-10 Induces Mouse Mast Cell Apoptosis

doi:10.1084/jem.192.8.1093

Published online 9 October 2000.

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© The Rockefeller University Press, 0022-1007/2000/10/1093/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1093-1104

Original Article

Combined Stimulation with the T Helper Cell Type 2 Cytokines Interleukin (IL)-4 and IL-10 Induces Mouse Mast Cell Apoptosis

C. Fitzhugh Yeatman, II^a, Sarah M. Jacobs-Helber^b, Paria Mirmonsef^a, Sheila R. Gillespie^a, Lawrence Andrew Bouton^a, Henrietta A. Collins^a, Stephen T. Sawyer^b, Christopher P. Shelburne^a, and John J. Ryan^a
^a Department of Biology, Virginia Commonwealth University, Richmond, Virginia 23284
^b Department of Pharmacology/Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298

Correspondence to: John J. Ryan, Dept. of Biology, Box 842012, Virginia Commonwealth University, Richmond, VA 23284-2012. Tel:804-225-3456 Fax:804-828-0503

Mast cells are found in connective and mucosal tissues throughoutthe body. Their activation via immunoglobulin E (IgE)–antigeninteractions is promoted by T helper cell type 2 (Th2) cytokinesand leads to the sequelae of allergic disease. We now reporta mechanism by which Th2 cytokines can regulate mast cell survival.Specifically, we find that interleukin (IL)-4 and IL-10 induceapoptosis in IL-3–dependent bone marrow–derivedmast cells and peritoneal mast cells. This process required6 d of costimulation with IL-3, IL-4, and IL-10, and expressionof signal transducer and activator of transcription 6 (Stat6).Apoptosis was coupled with decreased expression of bcl-x_L andbcl-2. While this process occurred independent of the Fas pathway,culture in IL-3+IL-4+IL-10 greatly sensitized mast cells toFas-mediated death. Additionally, we found that IgE cross-linkageor stimulation with stem cell factor enhanced the apoptoticabilities of IL-4 and IL-10. Finally, IL-3–independentmastocytomas and mast cell lines were resistant to apoptosisinduced by IL-3+IL-4+IL-10. These data offer evidence of Th2cytokine–mediated homeostasis whereby these cytokinesboth elicit and limit allergic responses. Dysregulation of thispathway may play a role in allergic disease and mast cell tumorsurvival.

Key Words: interleukin 4, interleukin 10, mast cells, apoptosis, allergy

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