SEROTONIN-MEDIATED PRODUCTION OF INTERSTITIAL COLLAGENASE BY UTERINE SMOOTH-MUSCLE CELLS REQUIRES INERLEUKIN-1-ALPHA, BUT NOT INTERLEUKIN-1-BETA

The activation of the gene for interstitial collagenase in myometrial smooth muscle cells is absolutely dependent upon the presence of serot onin. Our previous studies investigating the mechanisms of this induct ion 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 induc tion of IL-1 is required for the subsequent induction of collagenase. These data provided compelling evidence that serotonin-induced IL-1 ac ts via an autocrine loop in activating the collagenase gene. The exper iments described here were designed to examine the potential role of e ach IL-1 isoform in collagenase production by using neutralizing antis era specific to each isoform of the cytokine, The antisera were examin ed 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 th e induction of the mRNA for collagenase and of the mRNAs for both IL-1 alpha and IL-1 beta, Western analysis indicated that detectable level s of IL-1 alpha protein, but not that of IL-1 beta, are produced at th e time of serotonin-dependent collagenase induction. In contrast, sign ificant levels of IL-1 beta protein are detected only when bacterial l ipopolysaccharide is added to the cells. Taken together, the results o f our study indicate that IL-1 alpha, but not IL-1 beta, plays an obli gatory role in multiple serotonin-mediated gene regulations in the myo metrial smooth muscle cell. In addition, the data suggest that IL-1 be ta production has the potential for modifying myometrial function in p athological settings, particularly that of uterine infection.