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* Dipartimento di Scienze e Tecnologie Biomediche;
Microgravity, Ageing, Training, Immobility, Center of Excellence, Università di Udine, Udine, Italy;
Molecular Inflammation Section Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Torino, Italy
Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H2O2) promotes IL-4 and IL-6 mRNA production and potentates Fc
RI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H2O2 treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H2O2 induce cytokine secretion and enhance IL-4 production upon FcRI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H2O2 induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H2O2-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production.
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 a grant from Ministero dell’Istruzione Università e Ricerca (PRIN 2005), Agenzia Spaziale Italiana. (Progetto OSMA), and LR.11 del Friuli Venezia Giulia.
2 Address correspondence and reprint requests to Dr. Carlo Pucillo, Immmunology Section, Department of Biomedical Science and Technology, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy. E-mail address: carlo.pucillo{at}uniud.it
3 Abbreviations used in this paper: BMMC, bone marrow-derived cultured mast cells; LAT, linker of activated T cells; ROS, reactive oxygen species; SCF, stem cell factor.
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