Neki R, Matsuzaki N, Yamanaka K, Shimoya K, Okada T, Saji F, Iwashita M, Tanizawa O
Department of Obstetrics and Gynecology, Osaka University Medical School, Japan.
J Clin Endocrinol Metab. 1993 Sep;77(3):704-9. doi: 10.1210/jcem.77.3.8370693.
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.
白细胞介素-6（IL-6）可能通过激活人滋养层细胞上的IL-6受体（-R）系统在人绒毛膜促性腺激素（hCG）产生中发挥重要作用。滋养层细胞对重组IL-6（rIL-6）以及8-溴环磷酸腺苷（8-Br-cAMP）、12-O-十四酰佛波醇-13-乙酸酯（TPA）和钙离子载体A23187产生反应而分泌hCG。为了确定IL-6-R系统激活的信号转导途径是否依赖于蛋白激酶，如蛋白激酶A、蛋白激酶C和Ca2+/钙调蛋白依赖性激酶，在存在或不存在蛋白激酶抑制剂如N（2-甲基氨基乙基）-5-异喹啉磺酰胺二盐酸盐（H8）、1-（5-异喹啉磺酰基）-2-甲基哌嗪（H7）和钙调蛋白拮抗剂N-（6-氨基己基）-5-氯-1-萘磺酰胺（W7）的情况下，用重组（r-）IL-6刺激滋养层细胞。H8、H7和W7未能抑制rIL-6诱导的hCG产生，但分别完全抑制了8-Br-cAMP、TPA和促性腺激素释放激素激动剂（GnRHa）诱导的hCG产生。相反，酪氨酸激酶抑制剂染料木黄酮完全抑制rIL-6诱导的hCG产生，但未能抑制8-Br-cAMP、TPA和A23187诱导的hCG产生。染料木黄酮也未抑制GnRH诱导的hCG产生。将染料木黄酮添加到rIL-1和rTNF-α刺激的滋养层细胞中，可抑制rIL-1诱导和rTNF-α诱导的hCG产生，但维持rIL-1和rTNF-α诱导的IL-6产生。这些结果表明，胎盘中IL-6/IL-6-R系统诱导的信号转导途径可能通过激活酪氨酸激酶途径刺激hCG产生。染料木黄酮实验表明，GnRH/GnRH-R系统激活的信号转导途径与IL-6/IL-6-R系统激活的途径不同。
