title: 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.
abstract: Interleukin-6 (IL-6) may play an important role in human CG (hCG) production by activating the IL-6-receptor (-R) system on human trophoblasts. Trophoblasts produced hCG in response to rIL-6 as well as to 8-bromo 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 such as protein kinase A, protein kinase C, and Ca2+/calmodulin-dependent kinase, trophoblasts were stimulated with recombinant (r-) IL-6 in the 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 antagonist, N-(6-aminohexyl)-5-chloro-1- napthalenesulfonamide (W7), H8, H7, and W7 failed to suppress rIL-6-induced hCG production but completely inhibited hCG production induced by 8-Br-cAMP, TPA, and the GnRH agonist (GnRHa), respectively. In contrast, genistein, a tyrosine kinase inhibitor, completely suppressed rIL-6-induced hCG production but failed to inhibit hCG production induced by 8-Br-cAMP, TPA, and A23187. Genistein also did not suppress GnRH-induced hCG production. The addition of genistein to rIL-1- and rTNF-alpha-stimulated trophoblasts inhibited rIL-1-induced and rTNF-alpha induced hCG production but maintained rIL-1- and rTNF-alpha-induced IL-6 production. These results show that the IL-6/IL-6-R system-induced signal transduction pathway in the placenta probably stimulates hCG production by activating a tyrosine kinase pathway. The experiment with genistein shows that the GnRH/GnRH-R system activates a signal transduction pathway distinct from that activated by the IL-6/IL-6-R system.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Medical School, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Neki
authors.forename: N
authors.initials: N
authors.lastname: Matsuzaki
authors.forename: K
authors.initials: K
authors.lastname: Yamanaka
authors.forename: K
authors.initials: K
authors.lastname: Shimoya
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: F
authors.initials: F
authors.lastname: Saji
authors.forename: M
authors.initials: M
authors.lastname: Iwashita
authors.forename: O
authors.initials: O
authors.lastname: Tanizawa
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D006063:Chorionic Gonadotropin / Q000096:biosynthesis*; D004789:Enzyme Activation; D005260:Female; D019833:Genistein; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D007529:Isoflavones / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002147:Calmodulin; D006063:Chorionic Gonadotropin; D007375:Interleukin-1; D015850:Interleukin-6; D007529:Isoflavones; D047428:Protein Kinase Inhibitors; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007987:Gonadotropin-Releasing Hormone; D000001:Calcimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate