The Journal of Experimental Medicine
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Published 17 May 2004. doi:10.1084/jem.20031666
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1317-1330
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Uteroglobin Represses Allergen-induced Inflammatory Response by Blocking PGD2 Receptor–mediated Functions

Asim K. Mandal1, Zhongjian Zhang1, Rabindranath Ray1, Moonsuk S. Choi1, Bhabadeb Chowdhury1, Nagarajan Pattabiraman2, and Anil B. Mukherjee1

1 Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892
2 Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057

Address correspondence to Anil B. Mukherjee, Bldg. 10, Rm. 9S241, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-7213; Fax: (301) 402-6632; email: mukherja{at}exchange.nih.gov

Uteroglobin (UG) is an antiinflammatory protein secreted by the epithelial lining of all organs communicating with the external environment. We reported previously that UG-knockout mice manifest exaggerated inflammatory response to allergen, characterized by increased eotaxin and Th2 cytokine gene expression, and eosinophil infiltration in the lungs. In this study, we uncovered that the airway epithelia of these mice also express high levels of cyclooxygenase (COX)-2, a key enzyme for the production of proinflammatory lipid mediators, and the bronchoalveolar lavage fluid (BALF) contain elevated levels of prostaglandin D2. These effects are abrogated by recombinant UG treatment. Although it has been reported that prostaglandin D2 mediates allergic inflammation via its receptor, DP, neither the molecular mechanism(s) of DP signaling nor the mechanism by which UG suppresses DP-mediated inflammatory response are clearly understood. Here we report that DP signaling is mediated via p38 mitogen–activated protein kinase, p44/42 mitogen–activated protein kinase, and protein kinase C pathways in a cell type–specific manner leading to nuclear factor–{kappa}B activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor–{kappa}B activation and suppresses COX-2 gene expression. We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses.

Key Words: allergic airway inflammation • uteroglobin • Th2 cytokines • eosinophils • secretoglobin

A.K. Mandal, Z. Zhang, and R. Ray contributed equally to this work.

The online version of this article contains supplemental material.

A.K. Mandal's present address is Dept. of Medicine/Renal Unit, Harvard Medical School and Massachusetts General Hospital-East, Charlestown, MA 02129.

Abbreviations used in this paper: AA, arachidonic acid; BALF, bronchoalveolar lavage fluid; COX, cyclooxygenase; EMSA, electrophoretic mobility shift analysis; MAPK, mitogen-activated protein kinase; MG, myoglobin; OVA, ovalbumin; PGD2, prostaglandin D2; PKC, protein kinase C; rUG, recombinase UG; UG, uteroglobin.


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