Serotonin-mediated Production of Interstitial Collagenase by Uterine Smooth Muscle Cells Requires Interleukin-1α, but Not Interleukin-1β

The activation of the gene for interstitial collagenase in myometrial smooth muscle cells is absolutely dependent upon the presence of serotonin. Our previous studies investigating the mechanisms of this induction demonstrated that the mRNAs of both interleukin-1 (IL-1) isoforms, IL-1 alpha and IL-1 beta, are induced by serotonin and that the induction of IL-1 is required for the subsequent induction of collagenase. These data provided compelling evidence that serotonin-induced IL-1 acts via an autocrine loop in activating the collagenase gene. The experiments described here were designed to examine the potential role of each IL-1 isoform in collagenase production by using neutralizing antisera specific to each isoform of the cytokine, The antisera were examined for their ability to inhibit the serotonin-dependent production of the mRNA for collagenase and of the cytokines themselves. Neutralizing antiserum against IL-1 alpha, but not against IL-1 beta, inhibited the induction of the mRNA for collagenase and of the mRNAs for both IL-1 alpha and IL-1 beta, Western analysis indicated that detectable levels of IL-1 alpha protein, but not that of IL-1 beta, are produced at the time of serotonin-dependent collagenase induction. In contrast, significant levels of IL-1 beta protein are detected only when bacterial lipopolysaccharide is added to the cells. Taken together, the results of our study indicate that IL-1 alpha, but not IL-1 beta, plays an obligatory role in multiple serotonin-mediated gene regulations in the myometrial smooth muscle cell. In addition, the data suggest that IL-1 beta production has the potential for modifying myometrial function in pathological settings, particularly that of uterine infection.