Synergistic effect of vasoactive intestinal peptides on TNF-α-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation

  • Authors:
    • Hideo Natsume
    • Haruhiko Tokuda
    • Jun Mizutani
    • Seiji Adachi
    • Rie Matsushima-Nishiwaki
    • Chiho Minamitani
    • Kenji Kato
    • Osamu Kozawa
    • Takanobu Otsuka
  • View Affiliations

  • Published online on: May 1, 2010     https://doi.org/10.3892/ijmm_00000409
  • Pages: 813-817
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Abstract

We previously showed that tumor necrosis factor-α (TNF-α) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of vasoactive intestinal peptide (VIP) on TNF-α-induced IL-6 synthesis in these cells. VIP, which by itself slightly stimulated IL-6 synthesis, synergistically enhanced the TNF-α-induced IL-6 synthesis in MC3T3-E1 cells. The synergistic effect of VIP on the TNF-α-induced IL-6 synthesis was concentration-dependent in the range between 1 and 70 nM. We previously reported that VIP stimulated cAMP production in MC3T3-E1 cells. Forskolin, a direct activator of adenylyl cyclase, or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP), a plasma membrane-permeable cAMP analogue, markedly enhanced the TNF-α-induced IL-6 synthesis as well as VIP. VIP markedly up-regulated the TNF-α-induced p44/p42 MAP kinase phosphorylation. The Akt phosphorylation stimulated by TNF-α was only slightly affected by VIP. PD98059, a specific inhibitor of MEK1/2, significantly suppressed the enhancement of TNF-α-induced IL-6 synthesis by VIP. The synergistic effect of a combination of VIP and TNF-α on the phosphorylation of p44/p42 MAP kinase was diminished by H-89, an inhibitor of cAMP-dependent protein kinase. These results strongly suggest that VIP synergistically enhances TNF-α-stimulated IL-6 synthesis via up-regulating p44/p42 MAP kinase through the adenylyl cyclase-cAMP system in osteoblasts.

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May 2010
Volume 25 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Natsume H, Tokuda H, Mizutani J, Adachi S, Matsushima-Nishiwaki R, Minamitani C, Kato K, Kozawa O and Otsuka T: Synergistic effect of vasoactive intestinal peptides on TNF-α-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation. Int J Mol Med 25: 813-817, 2010
APA
Natsume, H., Tokuda, H., Mizutani, J., Adachi, S., Matsushima-Nishiwaki, R., Minamitani, C. ... Otsuka, T. (2010). Synergistic effect of vasoactive intestinal peptides on TNF-α-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation. International Journal of Molecular Medicine, 25, 813-817. https://doi.org/10.3892/ijmm_00000409
MLA
Natsume, H., Tokuda, H., Mizutani, J., Adachi, S., Matsushima-Nishiwaki, R., Minamitani, C., Kato, K., Kozawa, O., Otsuka, T."Synergistic effect of vasoactive intestinal peptides on TNF-α-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation". International Journal of Molecular Medicine 25.5 (2010): 813-817.
Chicago
Natsume, H., Tokuda, H., Mizutani, J., Adachi, S., Matsushima-Nishiwaki, R., Minamitani, C., Kato, K., Kozawa, O., Otsuka, T."Synergistic effect of vasoactive intestinal peptides on TNF-α-induced IL-6 synthesis in osteoblasts: amplification of p44/p42 MAP kinase activation". International Journal of Molecular Medicine 25, no. 5 (2010): 813-817. https://doi.org/10.3892/ijmm_00000409