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Mitochondrial Uncoupling Protein 2 Inhibits Mast Cell Activation and Reduces Histamine Content¹

Michael Tagen,^2* Alvaro Elorza, Duraisamy Kempuraj,^* William Boucher,^* Christopher L. Kepley,^¶ Orian S. Shirihai, and Theoharis C. Theoharides^3*

^*Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Pharmacology and Experimental Therapeutics, Department of Biochemistry, and Department of Internal Medicine. Tufts University School of Medicine, Tufts Medical Center, Boston, MA 02111; Department of Medicine, Boston University School of Medicine, Boston, MA 02118; and ^¶Luna Innovations Inc., Danville, VA 24541

Mast cells are immune effector cells that are involved in allergies and inflammation through the release of mediators such as histamine, PGs, and cytokines. Uncoupling protein 2 (UCP2) is a mitochondrial protein that inhibits insulin secretion from β cells, possibly through down-regulation of reactive oxygen species production. We hypothesized that UCP2 could also regulate mast cell activation. In this study, we show that mouse bone marrow mast cells (BMMCs) and human leukemic LAD2 mast cells express UCP2. BMMCs from Ucp2^–/– mice exhibited greater histamine release, whereas overexpression of UCP2 in LAD2 cells reduced histamine release after both allergic and nonallergic triggers. Ucp2^–/– BMMCs also had elevated histamine content and histidine decarboxylase expression. Histamine content was reduced by overexpression of UCP2 or treatment with the mitochondrial-targeted superoxide dismutase-mimetic (TBAP) tetrakis(4-benzoic acid) porphyrin manganese(III). Furthermore, Ucp2^–/– BMMCs also had greater production of both IL-6 and PGD₂ as well as ERK phosphorylation, which is known to regulate PG synthesis. Intradermal administration of substance P, an activator of skin mast cells, and challenge with DNP-human serum albumin after passive sensitization induced significantly greater vascular permeability in the skin of Ucp2^–/– mice in vivo. Our results suggest that UCP2 can regulate mast cell 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 in part by the National Institutes of Health (Grant 2R01 AR047652 to T.C.T.).

² Current address: Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105.

³ Address correspondence and reprint requests to Dr. Theoharis C. Theoharides, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. E-mail address: theoharis.theoharides{at}tufts.edu

⁴ Abbreviations used in this paper: SP, substance P; BMMCs, bone marrow mast cell; C48/80, compound 48/80; HSA, human serum albumin; EB, Evans blue; FSMC, fetal skin mast cell; HDC, histidine decarboxylase; SOD, superoxide dismutase; ROS, reactive oxygen species; UCP, uncoupling protein; SCF, stem cell factor; TBAP, tetrakis(4-benzoic acid) porphyrin.