ADRENOMEDULLIN STIMULATES INTERLEUKIN-6 PRODUCTION IN SWISS 3T3 CELLS

Adrenomedullin (AM) has very recently been demonstrated to be produced and secreted from fibroblasts. The production of AAI in the fibroblas ts is augmented by inflammation-related substances, and Swiss 3T3 fibr oblast cells express AM specific receptors coupled with adenylate cycl ase. To assess the functions of AM secreted from fibroblasts, we measu red the effect of AM on production in Swiss 3T3 cells of interleukin-6 (IL-6), a typical cytokine involved in the general inflammatory react ions, AM stimulated basal secretion of IL-6 5.5-fold, while other pept ides elicited much weaker stimulatory effects. The effect of AM was in hibited with an AM receptor antagonist and a cAMP-dependent protein ki nase (PKA) inhibitor, Furthermore, AM remarkably potentiated stimulato ry effects of tumor necrosis factor-alpha, IL-1 beta and lipopolysacch aride on IL-6 production, This stimulatory effect of AM was induced th rough activation of gene transcription, which reached maximum within 3 0 min, These findings verify that AM is a rapid and extraordinarily po tent regulator of IL-6 production in Swiss 3T3 cells acting through th e cAMP-PKA pathway, The data thus obtained suggest that AM is a peptid ergic regulator of inflammation. (C) 1998 Academic Press.