THE INTERLEUKIN-6 (IL-6) IL-6-RECEPTOR SYSTEM INDUCES HUMAN CHORIONIC-GONADOTROPIN PRODUCTION BY ACTIVATING TYROSINE KINASE-DEPENDENT SIGNAL-TRANSDUCTION PATHWAY DIFFERENT FROM PATHWAYS TRIGGERED BY PROTEIN-KINASE ACTIVATORS INCLUDING GONADOTROPIN-RELEASING-HORMONE/

Interleukin-6 (IL-6) may play an important role in human CG (hCG) prod uction by activating the IL-6-receptor (-R) system on human trophoblas ts. Trophoblasts produced hCG in response to rIL-6 as well as to 8-bro mo cAMP (8-Br-cAMP), 12-O-tetradecanoyl phorbol-13-acetate (TPA), and calcium ionophore A23187. To determine whether the signal transduction pathway activated by the IL-6-R system depends on protein kinases suc h as protein kinase A, protein kinase C, and Ca2+/calmodulin-dependent kinase, trophoblasts were stimulated with recombinant (r-) IL-6 in th e presence or absence of protein kinase inhibitors such as N(2-methyl- aminoethyl)-5-isoquinoline sulfonamide dihydrochloride (H8), and 1-(5- isoquinolinesulfomyl)-2-methylpiperazine (H7) and a calmodulin antagon ist, N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide (W7), H8, H7, a nd W7 failed to suppress rIL-6-induced hCG production but completely i nhibited hCG production induced by 8-Br-cAMP, TPA, and the GnRH agonis t (GnRHa), respectively. In contrast, genistein, a tyrosine kinase inh ibitor, completely suppressed rIL-6-induced hCG production but failed to inhibit hCG production induced by 8-Br-cAMP, TPA, and A23187. Genis tein also did not suppress GnRH-induced hCG production. The addition o f genistein to rIL-1- and rTNF-alpha-stimulated trophoblasts inhibited rIL-1-induced and rTNF-alpha-induced hCG production but maintained rI L-1- and rTNF-alpha-induced IL-6 production. These results show that t he IL-6/IL-6-R system-induced signal transduction pathway in the place nta probably stimulates hCG production by activating a tyrosine kinase pathway. The experiment with genistein shows that the GnRH/GnRH-R sys tem activates a signal transduction pathway distinct from that activat ed by the IL-6/IL-6-R system.