Uteroglobin Inhibits Prostaglandin F2α Receptor-mediated Expression of Genes Critical for the Production of Pro-inflammatory Lipid Mediators

Asim K Mandal,Rabindranath Ray,Zhongjian Zhang,Bhabadeb Chowdhury,Nagarajan Pattabiraman,Anil B Mukherjee

doi:10.1074/jbc.m502375200

Abstract

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 F2alpha (PGF2alpha). The biological effects of PGF2alpha 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 PGF2alpha 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-kappaB, 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 PGF2alpha. Most importantly, uteroglobin inhibits FP-mediated NF-kappaB activation and cyclooxygenase-2 gene expression by binding and most likely by sequestering PGF2alpha into its central hydrophobic cavity, thereby preventing FP-PGF2alpha 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.

Highlights

Uteroglobin (UG),4 known as Clara cell 10-kDa protein (CC10), is a founding member of the secretoglobin superfamily [1]
We found that PGF2␣, in a time-dependent manner, stimulates COX-2 mRNA and COX-2 protein expression in both hUSM (Fig. 1A) and NIH 3T3 (Fig. 1B) cells
Our results show that PGF2␣ stimulates the expression of cytosolic PLA2 (cPLA2) mRNA (Fig. 3A) and protein (Fig. 3B) suggesting that FP signaling may regulate AA release from cellular phospholipids mediated by cPLA2 catalysis

Summary

Introduction

Uteroglobin (UG),4 known as Clara cell 10-kDa protein (CC10), is a founding member of the secretoglobin superfamily [1]. 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, stimulating the expression of cyclooxygenase-2. These results suggest that in hUSM and NIH 3T3 cells PGF2␣ stimulates COX-2 gene expression.

Results

Conclusion