Uteroglobin inhibits prostaglandin F2alpha receptor-mediated expression of genes critical for the production of pro-inflammatory lipid mediators.
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.
Mandal
Asim K
AK
Section on Developmental Genetics, Heritable Disorders Branch, NICHD, The National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Ray
Rabindranath
R
Zhang
Zhongjian
Z
Chowdhury
Bhabadeb
B
Pattabiraman
Nagarajan
N
Mukherjee
Anil B
AB
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D051379:Mice; D008958:Models, Molecular; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014598:Uteroglobin / Q000378:metabolism / Q000502:physiology*; D014599:Uterus / Q000378:metabolism / Q000473:pathology
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D016718:Arachidonic Acid; D012313:RNA; D014598:Uteroglobin