Cytokines Regulate Matrix Metalloproteinases in Human Uterine Endometrial Fibroblast Cells Through a Mechanism That Does Not Involve Increases in Extracellular Matrix Metalloproteinase Inducer

Andrea Braundmeier, Andrea G Braundmeier, Braundmeier AG, Nowak RA, Romana A. Nowak
American journal of reproductive immunology (New York, N.Y. : 1989) · 2006 · vol. 56(3) , pp. 201–214 · doi:10.1111/j.1600-0897.2006.00418.x · PMID:16911716 · W2059790490
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Cytokines IL-1beta and TNF-alpha stimulate MMP-1, -2, and -3 production in human uterine fibroblasts, while TGF-beta(1) inhibits MMP-1 and -2 mRNA, all without altering EMMPRIN expression.

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Abstract

PROBLEM: Endometriosis is the presence of ectopic uterine endometrial tissue in the peritoneal cavity. Peritoneal fluid samples of women with endometriosis show elevated interleukin-1 (IL-1)beta, tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta(1) levels, indicating that an altered immune system may play an important role in the pathogenesis of endometriosis. The invasion of ectopic endometrium into peritoneal mesothelium requires matrix metalloproteinases (MMPs) for tissue remodeling. Several MMPs are differentially expressed in human uterine endometrium with menstrual endometrium showing the highest level of expression. MMPs are stimulated by cytokines and also by the protein Extracellular Matrix Metalloproteinase Inducer (EMMPRIN). METHOD OF STUDY: To determine the role of cytokines in ectopic endometrial invasion, we investigated whether cytokines could regulate MMP production by endometrial fibroblast cells and whether this stimulation occurred through an effect on EMMPRIN expression. Human uterine fibroblasts (HUF) were treated with IL-1beta, TGF-beta(1) and TNF-alpha in a dose dependent and time dependent manner (C, 0.1, 1, 10 ng/mL IL-1beta or TGF-beta(1); C, 2, 10, 50 ng/mL TNF-alpha) for 0, 6, 12, and 24 hr. Cell conditioned medium samples were collected and concentrated at each timepoint for immunoblot analysis. Cellular RNA was collected for real time PCR analysis of MMPs-1, -2, -3 and EMMPRIN mRNA levels. RESULTS: Our results showed that IL-1beta stimulated MMP-1 protein secretion and mRNA levels in a time dependent manner (P < 0.05), MMP-2 mRNA in a time dependent manner and MMP-3 in a time and dose dependent manner. TNF-alpha stimulated MMP-1 and -3 protein secretion in a time dependent manner and stimulated MMP-1, -2 and -3 mRNA levels in a time dependent manner (P < 0.05). Neither IL-1beta nor TNF-alpha treatment affected MMP-2 protein secretion. TGF-beta(1) inhibited MMP-1 and MMP-2 mRNAs at the highest treatment dose after 24 hr but there was no effect on protein secretion. TGF-beta(1) exerted no effect on MMP-3 mRNA or protein secretion (P < 0.05). Neither of the cytokines affected EMMPRIN protein or mRNA levels but the 10 ng/mL TGF-beta(1) treatment did cause a reduction in EMMPRIN mRNA levels. CONCLUSIONS: These data show that elevated cytokines may play a role in the establishment of ectopic endometrium in the peritoneal cavity by stimulating MMPs to remodel the mesothelial lining of the peritoneum thus allowing for tissue invasion. The stimulation of MMPs by cytokines occurred without any change in EMMPRIN expression whereas the inhibitory effect of TGF-beta(1) involved a reduction in EMMPRIN mRNA levels.

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Condition tags

endometriosis

MeSH descriptors

Basigin Cytokines Endometrium Matrix Metalloproteinases Basigin Basigin Cell Line Cells, Cultured Cell Separation Cytokines Cytokines Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Female Fibroblasts Fibroblasts

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