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Calcitonin Induces IL-6 Production via Both PKA and PKC Pathways in the Pituitary Folliculo-Stellate Cell Line

Department of Physiological Chemistry (Y.K.) and Laboratory of Molecular Design of Pharmaceutics (H.T.), Graduate School of Pharmaceutical Sciences, Hokkaido University; and Department of Laboratory Medicine, Hokkaido University Graduate School of Medicine (T.M.), Sapporo 060-0812, Japan; Department of Pharmacology, Hokkaido College of Pharmacy (K.S.), Otaru 047-0264, Japan; and Health Sciences University of Hokkaido (Y.T.), Ishikari-Tobetsu 061-0293, Japan

Address all correspondence and requests for reprints to: Yukiko Tokumitsu, Ph.D., Health Sciences University of Hokkaido, IshikariTobetsu 061-0293, Japan. E-mail: tyukiko{at}hoku-iryo-u.ac.jp

It has been demonstrated that calcitonin-binding sites are present in a variety of tissue types, including in the pituitary gland. Interleukin-6 (IL-6) is also produced in the pituitary and it regulates the secretion of various hormones. In this study, we examined the expression of the calcitonin receptor and the mechanism of IL-6 production induced by calcitonin in the pituitary folliculo-stellate cell line (TtT/GF). The mRNA of calcitonin receptor subtype C1a, but not that of C1b, was detected by RT-PCR in TtT/GF cells and in the normal mouse pituitary. Calcitonin increased cAMP accumulation and IL-6 production in a concentration-dependent manner in TtT/GF cells. As calcitonin activates the PKA and PKC pathways, we investigated the contributions of PKA and PKC to IL-6 production. IL-6 production was only slightly increased by either 8-bromo-cAMP (1 mM) or phorbol 12-myristate 13-acetate (100 nM) alone. However, IL-6 was synergistically induced in the presence of both 8-bromo-cAMP (1 mM) and phorbol 12myristate 13-acetate (100 nM). Furthermore, calcitonin-induced IL-6 production was completely suppressed by H-89 (PKA inhibitor) or GF109203X (PKC inhibitor), indicating that the activation of both PKA and PKC is necessary for calcitonin-induced IL-6 production. On the other hand, pertussis toxin (G_i/G_o signaling inhibitor) treatment achieved an approximately 9-fold increase in calcitonin-induced IL-6 production. These results show that calcitonin-stimulated IL-6 production is mediated via both PKA- and PKC-signaling pathways, whereas calcitonin also suppresses IL-6 production by activating G_i/G_o proteins in folliculo-stellate cells.

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