DUSP-1 Induced by PGE2 and PGE1 Attenuates IL-1β-Activated MAPK Signaling,Leading to Suppression of NGF Expression in Human Intervertebral Disc Cells |
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Authors: | Takuya Kusakabe Yasunobu Sawaji Kenji Endo Hidekazu Suzuki Takamitsu Konishi Asato Maekawa Kazuma Murata Kengo Yamamoto |
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Affiliation: | Department of Orthopedic Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; (T.K.); (K.E.); (H.S.); (T.K.); (A.M.); (K.M.); (K.Y.) |
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Abstract: | The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory mediator prostaglandin E2 (PGE2), which is induced by inflammatory stimuli, such as interleukin-1β (IL-1β). However, in our previous in vitro study using cultured human IVD cells, we demonstrated that the induction of NGF by IL-1β is augmented by a selective COX-2 inhibitor, and that PGE2 and PGE1 suppress NGF expression. Therefore, in this study, to elucidate the mechanism of NGF suppression by PGE2 and PGE1, we focused on mitogen-activated protein kinases (MAPKs) and its phosphatase, dual-specificity phosphatase (DUSP)-1. IL-1β-induced NGF expression was altered in human IVD cells by MAPK pathway inhibitors. PGE2 and PGE1 enhanced IL-1β-induced DUSP-1 expression, and suppressed the phosphorylation of MAPKs in human IVD cells. In DUSP-1 knockdown cells established using small interfering RNA, IL-1β-induced phosphorylation of MAPKs was enhanced and prolonged, and NGF expression was significantly enhanced. These results suggest that PGE2 and PGE1 suppress IL-1β-induced NGF expression by suppression of the MAPK signaling pathway, accompanied by increased DUSP-1 expression. |
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Keywords: | dual-specificity phosphatase (DUSP)-1 prostaglandin E2 (PGE2) prostaglandin E1 (PGE1) interleukin-1β (IL-1β ) mitogen-activated protein kinase (MAPK) nerve growth factor (NGF) intervertebral disc (IVD) |
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