Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells

Since uterine cervical ripening is an active biochemical process similar in part to an inflammatory reaction, nitric oxide (NO) has been proposed as a key mediator of this event. However, the mechanism by which NO modulates human cervical ripening has not been fully elucidated. In the present study we investigated the presence of NO synthases in human uterine cervix by immunohistochemistry and reverse transcriptase-polymerase chain reaction analysis. Furthermore, we examined the presence of NO-mediated regulation of matrix metalloproteinase-1 (MMP-1) production in cultured human uterine cervical fibroblast cells using enzyme-linked immunosorbent assay and Northern blot analysis. Endothelial and inducible NO synthases were detected in the form of mRNA and protein expression in pregnant uterine cervix. Interleukin-1alpha (IL-1alpha) increased the expression of inducible NO synthase mRNA in cultured human uterine cervical fibroblast cells. IL-1alpha also increased MMP-1 secretion from the cultured cervical fibroblast cells. This IL-1alpha-augmented MMP-1 secretion was partially but significantly blocked by an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester. On the other hand, NO donors increased MMP-1 production in the cultured cervical fibroblast cells. These findings together suggest that NO contributes to the process of cervical ripening via enhancement of MMP-1 production, and that IL-1alpha increases MMP-1 secretion from cervical fibroblasts at least in part via NO synthesis.