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J. Biol. Chem., Vol. 280, Issue 38, 32897-32904, September 23, 2005

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Uteroglobin Inhibits Prostaglandin F₂ Receptor-mediated Expression of Genes Critical for the Production of Pro-inflammatory Lipid Mediators^*

Asim K. Mandal12, Rabindranath Ray1, Zhongjian Zhang, Bhabadeb Chowdhury, Nagarajan Pattabiraman, and Anil B. Mukherjee3

From the Section on Developmental Genetics, Heritable Disorders Branch, NICHD, The National Institutes of Health, Bethesda, Maryland 20892-1830 and the Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D. C. 20057-1421

Prematurity is one of the leading causes of infant mortality. It may result from intrauterine infection, which mediates premature labor by stimulating the production of inflammatory lipid mediators such as prostaglandin F₂ (PGF₂). The biological effects of PGF₂ are mediated via the G protein-coupled receptor FP; however, the molecular mechanism(s) of FP signaling that mediates inflammatory lipid mediator production remains unclear. We reported previously that in the human uterus, a composite organ in which fibroblast, epithelial, and smooth muscle cells are the major constituents, an inverse relationship exists between the levels of PGF₂ and a steroid-inducible anti-inflammatory protein, uteroglobin. Here we report that, in NIH 3T3 fibroblasts and human uterine smooth muscle cells, FP signaling is mediated via multi-kinase pathways in a cell type-specific manner to activate NF-B, thus stimulating the expression of cyclooxygenase-2. Cyclooxygenase-2 is a critical enzyme for the production of prostaglandins from arachidonic acid, which is released from membrane phospholipids by phospholipase A₂, the expression of which is also stimulated by PGF₂. Most importantly, uteroglobin inhibits FP-mediated NF-B activation and cyclooxygenase-2 gene expression by binding and most likely by sequestering PGF₂ into its central hydrophobic cavity, thereby preventing FP-PGF₂ interaction and suppressing the production of inflammatory lipid mediators. We propose that uteroglobin plays important roles in maintaining homeostasis in organs that are vulnerable to inadvertent stimulation of FP-mediated inflammatory response.

Received for publication, March 3, 2005 , and in revised form, June 29, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Dept. of Medicine/Renal Unit, Harvard Medical School and Massachusetts General Hospital-East, Charlestown, MA 02129.

³ To whom correspondence should be addressed. E-mail: mukherja{at}exchange.nih.gov.

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				A. B. Mukherjee, Z. Zhang, and B. S. Chilton Uteroglobin: A Steroid-Inducible Immunomodulatory Protein That Founded the Secretoglobin Superfamily Endocr. Rev., December 1, 2007; 28(7): 707 - 725. [Abstract] [Full Text] [PDF]