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CARMA3 Mediates Lysophosphatidic Acid–Stimulated Cytokine Secretion by Bronchial Epithelial Cells

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 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-B activity in response to numerous stimuli. Here we demonstrate that CARMA3 (CARD10) is specifically expressed in human airway epithelial cells, and that expression of CARMA3 in these cells leads to activation of NF-B. CARMA3 has recently been shown to mediate NF-B activation in embryonic fibroblasts after stimulation with lysophosphatidic acid (LPA), a bioactive lipid-mediator that is elevated in the lungs of individuals with asthma. Consistent with this, we demonstrate that stimulation of airway epithelial cells with LPA leads to increased expression of TSLP and CCL20. We then show that inhibition of CARMA3 activity in airway epithelial cells reduces LPA-mediated NF-B activity and the production of TSLP and CCL20. In conclusion, these data demonstrate that LPA stimulates TSLP and CCL20 expression in bronchial epithelial cells via CARMA3-mediated NF-B activation.

Key Words: bronchial epithelial cells • asthma • lysophosphatidic acid • thymic stromal lymphopoietin • CARMA3

CLINICAL RELEVANCE We demonstrate that CARMA3 is highly expressed in airway epithelial cells and that it mediates thymic stromal lymphopoietin and CCL20 expression in response to lysophosphatidic acid stimulation. These data illuminate a novel inflammatory pathway that could be important in asthma pathogenesis.

 

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