SEROTONIN REGULATES THE EXPRESSION OF THE GENE FOR ALPHA(2)-MACROGLOBULIN IN MYOMETRIAL SMOOTH-MUSCLE CELLS

Serotonin (5-hydroxytryptamine (5-MT)) has been shown to be a regulato r of gene expression in rat myometrial smooth muscle cells (SMC). Sero tonin activates the genes for interstitial collagenase, irterleukin-1 alpha, -1 beta and interleukin-6, among others. On the other hand, ser otonin down-regulates the genes for types I and III collagen and fibro nectin. Here we show that serotonin is also a negative regulator of th e expression of anti-protease alpha(2)-macroglobulin (alpha(2)M) in SM C. The serotonin-dependent repression occurs at both the mRNA and prot ein levels, and is mediated by the 5-MT2A receptor subtype. The inhibi tory effect is prevented by cycloheximide, indicating the requirement for the synthesis of one or more proteins. Interleukin-1 (IL-1), which is induced by serotonin in SMC and is required for subsequent interst itial collagenase induction, appears not to be one of these intermedia tes. On the other hand, progesterone, the major steroid hormone of pre gnancy, is capable of reversing the serotonin-mediated inhibition of a lpha(2)M. The phorbol myristate acetate (PMA), which mimics the induct ion of interstitial collagenase by serotonin, fails to affect the inhi bition of a(2)M production. The cell-permeable cyclic AMP analogue 8-b romoadenosine 3':5'-cyclic monophosphate sodium salt (8-bromo-cAMP), i s, however, capable of fully reproducing the action of serotonin on al pha(2)M. These results further speak to the ability of serotonin to re gulate gene expression in he myometrial SMC, both positively and negat ively. In addition, although all the effects of serotonin so far ident ified are mediated by the 5-MT2A receptor, different post-receptor pat hways appear to mediate the positively and negatively regulated genes. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.