Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice.
The immunomodulatory role of arachidonic acid metabolites in allergic sensitization is undefined. Prostaglandin E(2) (PGE(2)), 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-1alpha, MIP-1beta, 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.
Peebles
R S
RS
Departments of Medicine, Pathology, and Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Dworski
R
R
Collins
R D
RD
Jarzecka
K
K
Mitchell
D B
DB
Graham
B S
BS
Sheller
J R
JR
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D019742:Chemokines, CC / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D006967:Hypersensitivity / Q000503:physiopathology*; D007073:Immunoglobulin E / Q000097:blood; D007213:Indomethacin / Q000494:pharmacology*; D018793:Interleukin-13 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000473:pathology; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000378:metabolism* / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms
D019742:Chemokines, CC; D016861:Cyclooxygenase Inhibitors; D018793:Interleukin-13; D015848:Interleukin-5; D015850:Interleukin-6; D016210:Methacholine Chloride; D015847:Interleukin-4; D016718:Arachidonic Acid; D007073:Immunoglobulin E; D010047:Ovalbumin; D007213:Indomethacin