Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice

The immunomodulatory role of arachidonic acid metabolites in allergic sensi tization is undefined. Prostaglandin E-2 (PGE(2)), a product of arachidonic acid metabolism through the cyclooxygenase pathway, has been reported to f avor Type 2-like cytokine secretion profiles in murine and human CD4(+) T c ells by inhibiting the production of Type 1-associated cytokines. On the ba sis of these in vitro data, we hypothesized that indomethacin, a nonselecti ve cyclooxygenase inhibitor, would diminish allergen-induced production of Type 2 cytokines in mice, and protect against airway hyperresponsiveness (A HR) to methacholine. We found that ovalbumin-sensitized mice that were trea ted 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) an d IL-13 (1,226 +/- 279 versus 475 +/- 65 pg/ml) in lung supernatants than m ice sensitized with ovalbumin alone (OVA mice), while levels of IL-4 and se rum 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 betw een the two groups in lung mRNA expression of eotaxin, MIP-1 alpha, MIP-1 b eta, or MIP-2. Histologic examination revealed greater pulmonary interstiti al eosinophilia in OVA-indomethacin mice as well. Contrary to our expectati ons, we conclude that in the BALB/c mouse, cyclooxygenase inhibition during allergen sensitization increases AHR, production of IL-5 and IL-13, and in terstitial eosinophilia.