Joshua Boyce

Co-director, Inflammation and Allergic Disease Research Section
Div. of Rheumatology, Immunology and Allergy
Brigham and Women’s Hospital
Smith Bldg., Rm. 626, 1 Jimmy Fund Way
Boston MA 02115

Phone: (617) 525-1261
Fax: (617) 525-1260
email: jboyce@rics.bwh.harvard.edu

6 Postdoctoral Fellows

This lab is focused on the mechanisms and receptors by which cysteinyl leukotrienes (cys-LTs) control and amplify cellular responses to antigen and pathogens. The cys-LTs (LTC4, LTD4, and LTE4) are lipid mediators of inflammation that are generated in abundance by cells of the innate immune system during host responses to pathogens, as well as in asthma and other allergic diseases. They are best known for their smooth muscle contractile functions through the cys-LT-selective G protein-coupled receptors (GPCRs) (respectively termed CysLT1R and CysLT2R). CysLT1R and CysLT2R are members of a large family of primordial GPCRs for nucleotides.

The cys-LTs also potently amplify mucosal eosinophilia and induce mast cell proliferation by poorly understood mechanisms. We have demonstrated that one of the nucleotide-selective GPCRs is also a previously unrecognized receptor for LTE4, the most stable and abundant of the cys-LTs. This GPCR induces signaling using the nuclear lipid receptor PPARγ, and is essential for the potentiative effects of LTE4 on mucosal inflammation and mast cell hyperplasia, a key even in the pathophysiology of asthma and allergic diseases.

We focus on three main areas of basic research: (i) mechanisms of allergic inflammation; (ii) mast cell development; and (iii) GPCR-mediated signal transduction. We employ complementary approaches using human and mouse mast cells, RNA interference to knock down the expression of individual GPCRs, and energy transfer methods to demonstrate interactions between GPCRs and with their cognate signaling molecules. We have generated strains of mice lacking GPCRs essential to the cys-LT and nucleotide-related components of the amplified immune response, and have developed models of asthma and other allergic diseases. Additionally, since the immune response to allergens parallels immunity to certain pathogens, we are studying the functions of the cys-LT and nucleotide-selective GPCRs in responses to intestinal helminths.

Papers & Publications:

Mellor EA, Austen KF, Boyce JA. Cysteinyl leukotrienes and uridine diphosphate induce cytokine generation by human mast cells through an interleukin 4-regulated pathway that is inhibited by leukotriene receptor antagonists. J Exp Med. 2002;195;583-592.

Feng CL, Mery AG, Beller EM, Favot CL, Boyce JA. Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor. J Immunol. 2004;173:7539-7547.

Jiang Y, Kanaoka Y, Feng CL, Nocka K, Rao S, Boyce JA. Cutting Edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-dependent signaling. J Immunol. 2006;177:2755-9.

Jiang Y, Feng C, Backskai B, Boyce JA. CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene-dependent mitogenic responses of mast cells. Blood 2007;100:3263-3270

Paruchuri S, Jiang Y, Feng C, Francis SA, Plutzky J, Boyce JA. Leukotriene E4 activates peroxisome proliferator activated receptor gamma and induces prostaglandin D2 generation by human mast cells. J Biol Chem 2008;283:16477-16487