CARMA3 Mediates Lysophosphatidic Acid–Stimulated Cytokine Secretion by Bronchial Epithelial Cells
Benjamin D. Medoff1,2,
Aimee L. Landry3,
Kelley A. Wittbold1,2,
Barry P. Sandall1,
Merran C. Derby3,
Zhifang Cao3,5,
Joe C. Adams4 and
Ramnik J. Xavier3,5
1 Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology; 2 Pulmonary and Critical Care Unit; 3 Center for Computational and Integrative Biology; and 5 Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; 4 Otopathology Laboratory and the Department of Otolaryngology, MA Eye and Ear Infirmary, and the Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts
Correspondence and requests for reprints should be addressed to Ramnik J. Xavier, M.D., Center for Computational and Integrative Biology, Massachusetts General Hospital, Simches Research Building, Room 7222, 185 Cambridge Street, Boston, MA 02114. E-mail: xavier{at}molbio.mgh.harvard.edu or bmedoff{at}partners.org
NF-B activation in bronchial epithelial cells is important forthe development of allergic airway inflammation, and may controlthe expression of critical mediators of allergic inflammationsuch as thymic stromal lymphopoietin (TSLP) and the chemokineCCL20. Members of the caspase recruitment domain (CARD) familyof proteins are differentially expressed in tissue and helpmediate NF-B activity in response to numerous stimuli. Herewe demonstrate that CARMA3 (CARD10) is specifically expressedin human airway epithelial cells, and that expression of CARMA3in these cells leads to activation of NF-B. CARMA3 has recentlybeen shown to mediate NF-B activation in embryonic fibroblastsafter stimulation with lysophosphatidic acid (LPA), a bioactivelipid-mediator that is elevated in the lungs of individualswith asthma. Consistent with this, we demonstrate that stimulationof airway epithelial cells with LPA leads to increased expressionof TSLP and CCL20. We then show that inhibition of CARMA3 activityin airway epithelial cells reduces LPA-mediated NF-B activityand the production of TSLP and CCL20. In conclusion, these datademonstrate that LPA stimulates TSLP and CCL20 expression inbronchial epithelial cells via CARMA3-mediated NF-B activation.
We demonstrate that CARMA3 is highly expressed in airway epithelialcells and that it mediates thymic stromal lymphopoietin andCCL20 expression in response to lysophosphatidic acid stimulation.These data illuminate a novel inflammatory pathway that couldbe important in asthma pathogenesis.
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B activation in bronchial epithelial cells is important for the development of allergic airway inflammation, and may control the expression of critical mediators of allergic inflammation such as thymic stromal lymphopoietin (TSLP) and the chemokine CCL20. Members of the caspase recruitment domain (CARD) family of proteins are differentially expressed in tissue and help mediate NF-
