Am. J. Respir. Crit. Care Med., Volume 162, Number 2, August 2000, 676-681

Cyclooxygenase Inhibition Increases Interleukin 5 and Interleukin 13 Production and Airway Hyperresponsiveness in Allergic Mice

R. STOKES PEEBLES Jr., RYSZARD DWORSKI, ROBERT D. COLLINS, KASIA JARZECKA, DAPHNE B. MITCHELL, BARNEY S. GRAHAM, and JAMES R. SHELLER

Departments of Medicine, Pathology, and Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee

The immunomodulatory role of arachidonic acid metabolites in allergic sensitization is undefined. Prostaglandin E₂ (PGE₂), a product of arachidonic acid metabolism through the cyclooxygenase pathway, has been reported to favor Type 2-like cytokine secretion profiles in murine and human CD4⁺ T cells by inhibiting the production of Type 1-associated cytokines. On the basis of these in vitro data, we hypothesized that indomethacin, a nonselective cyclooxygenase inhibitor, would diminish allergen-induced production of Type 2 cytokines in mice, and protect against airway hyperresponsiveness (AHR) to methacholine. We found that ovalbumin-sensitized mice that were treated with indomethacin (OVA-indomethacin mice) had significantly greater AHR (p < 0.05) and higher levels of IL-5 (176 ± 52 versus 66 ± 4 pg/ml) and IL-13 (1,226 ± 279 versus 475 ± 65 pg/ml) in lung supernatants than mice sensitized with ovalbumin alone (OVA mice), while levels of IL-4 and serum IgE were not different. Lung mRNA expression of the C-C chemokine MCP-1 was increased in OVA-indomethacin mice, while there was no difference between the two groups in lung mRNA expression of eotaxin, MIP-1, MIP-1, or MIP-2. Histologic examination revealed greater pulmonary interstitial eosinophilia in OVA-indomethacin mice as well. Contrary to our expectations, we conclude that in the BALB/c mouse, cyclooxygenase inhibition during allergen sensitization increases AHR, production of IL-5 and IL-13, and interstitial eosinophilia.

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