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J. Biol. Chem., Vol. 278, Issue 50, 50607-50614, December 12, 2003

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Tetrahydrobiopterin, a Critical Factor in the Production and Role of Nitric Oxide in Mast Cells^*

Mark Gilchrist, Christian Hesslinger¶, and A. Dean Befus||

From the Glaxo-Heritage Asthma Research Laboratory, Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada and ^¶Pharmazentrum Frankfurt, J. W. Goethe-University, Frankfurt 60590, Germany

Mast cells (MC) are biologically potent, ubiquitously distributed immune cells with fundamental roles in host integrity and disease. MC diversity and function is regulated by exogenous nitric oxide; however, the production and function of endogenously produced NO in MC is enigmatic. We used rat peritoneal MC (PMC) as an in vivo model to examine intracellular NO production. Live cell confocal analysis of PMC using the NO-sensitive probe diaminofluorescein showed distinct patterns of intracellular NO formation with either antigen (Ag)/IgE (short term) or interferon- (IFN-) (long term). Ag/IgE-induced NO production is preceded by increased intracellular Ca²⁺, implying constitutive nitric-oxide synthase (NOS) activity. NO formation inhibits MC degranulation. NOS has obligate requirements for tetrahydrobiopterin (BH₄), a product of GTP-cyclohydrolase I (CHI), IFN--stimulated PMC increased CHI mRNA, protein, and enzymatic activity, while decreasing CHI feedback regulatory protein mRNA, causing sustained NO production. Treatment with the CHI inhibitor, 2,4-diamino-6-hydroxypyrimidine, inhibited NO in both IFN- and Ag/IgE systems, increasing MC degranulation. Reconstitution with the exogenous BH₄ substrate, sepiapterin, restored NO formation and inhibited exocytosis. Thus, Ag/IgE and IFN- induced intracellular NO plays a key role in MC mediator release, and alterations in NOS activity via BH₄ availability may be critical to the heterogeneous responsiveness of MC.

Received for publication, July 18, 2003 , and in revised form, September 22, 2003.

^* This work was supported by a grant from the Canadian Institutes for Health Research. 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental video.

^|| AstraZeneca Canada Inc. Chair in Asthma Research.

Supported by a studentship from the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: Dept. of Medicine, Rm. 550 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada. Tel.: 780-492-1909; Fax: 780-492-5329; E-mail: mark.gilchrist{at}ualberta.ca.

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