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Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen

Nature Medicine volume 5, pages 900–906 (1999)Cite this article

Abstract

Intestinal inflammatory diseases are mediated by dysregulated immune responses to undefined luminal antigens. Feeding hen egg-white lysozyme to mice expressing a transgenic T-cell receptor that recognizes hen egg-white lysozyme peptide 46–61 resulted in no intestinal pathology; however, simultaneous administration of cyclooxygenase-2 inhibitors and dietary hen egg-white lysozyme resulted in increased proliferation of lamina propria mononuclear cells and crypt epithelial cells, crypt expansion and villus blunting. Lamina propria mononuclear cells produce high levels of cyclooxygenase-2-dependent arachidonic acid metabolites, which act as immunomodulators in the immune response to dietary antigen. These findings establish that cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.

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Figure 1: Histologic changes in the proximal small intestines of 3A9 TCRα–/– transgenic mice given indomethacin and oral HEL.
Figure 2: Indomethacin alters the antigen-specific proliferative response of LPMNCs from 3A9 TCRα–/– transgenic mice.
Figure 3: Non-*βTCR+ LPMNCs produce increased levels of PGE2 by a COX-2-dependent pathway.
Figure 4: PGE2 produced by LPMNCs by a COX-2-dependent pathway suppresses antigen-specific proliferation.
Figure 5: Histologic changes in the proximal small intestines of 3A9 TCRα–/– transgenic mice given the selective COX-2 inhibitor NS-398 and oral HEL.

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Acknowledgements

We thank J. McDonough for technical assistance; and K. Roth, E. Newberry and S. Amadeus for assistance with manuscript preparation. This work was supported by grants from the Charles E. Culpeper Foundation (R.G.L.), the American Digestive Health Foundation FFTA sponsored by Astra Merck (R.D.N.) and NIH grants DK-33165 and DK-55753 (W.F.S.). R.G.L. is a Charles E. Culpeper Foundation Scholar.

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Authors and Affiliations

  1. Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Rodney D. Newberry, William F. Stenson & Robin G. Lorenz

  2. Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Rodney D. Newberry & William F. Stenson

  3. Department of Pathology, Center for Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Robin G. Lorenz

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Correspondence to Robin G. Lorenz.

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Newberry, R., Stenson, W. & Lorenz, R. Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 5, 900–906 (1999). https://doi.org/10.1038/11341

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