Counteracting effect of TRPC1-associated CA2+ influx on TNF-α-induced COX-2-dependent prostaglandin E2 production in human colonic myofibroblasts

Lin Hai, Yasuhiro Kawarabayashi, Yuko Imai, Akira Honda, Ryuji Inoue

研究成果: ジャーナルへの寄稿学術誌査読

20 被引用数 (Scopus)

抄録

TNF-α-NF-κB signaling plays a central role in inflammation, apoptosis, and neoplasia. One major consequence of this signaling in the gut is increased production of prostaglandin E2 (PGE2) via cyclooxygenase-2 (COX-2) induction in myofibroblasts, which has been reported to be dependent on Ca2+. In this study, we explored a potential role of canonical transient receptor potential (TRPC) proteins in this Ca2+-mediated signaling using a human colonic myofibroblast cell line CCD-18Co. In CCD-18Co cell, treatment with TNF-α greatly enhanced Ca2+ influx induced by store depletion along with increased cell-surface expression of TRPC1 protein (but not of the other TRPC isoforms) and induction of a Gd3+-sensitive nonselective cationic conductance. Selective inhibition of TRPC1 expression by small interfering RNA (siRNA) or functionally effective TRPC1 antibody targeting the near-pore region of TRPC1 (T1E3) antagonized the enhancement of store-dependent Ca2+ influx by TNF-α, whereas potentiated TNF-α induced PGE2 production. Overexpression of TRPC1 in CCD-18Co produced opposite consequences. Inhibitors of NF-κB (curcumin, SN-50) attenuated TNF-α-induced enhancement of TRPC1 expression, store-dependent Ca2+ influx, and COX-2-dependent PGE2 production. In contrast, inhibition of calcineurin-nuclear factor of activated T-cell proteins (NFAT) signaling by FK506 or NFAT Activation Inhibitor III enhanced the PGE2 production without affecting TRPC1 expression and the Ca2+ influx. Finally, the suppression of store-dependent Ca2+ influx by T1E3 antibody or siRNA knockdown significantly facilitated TNF-α-induced NF-κB nuclear translocation. In aggregate, these results strongly suggest that, in colonic myofibroblasts, NF-κB and NFAT serve as important positive and negative transcriptional regulators of TNF-α-induced COX-2-dependent PGE2 production, respectively, at the downstream of TRPC1-associated Ca2+ influx.

本文言語英語
ページ(範囲)G356-G367
ジャーナルAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
301
2
DOI
出版ステータス出版済み - 8月 2011

!!!All Science Journal Classification (ASJC) codes

  • 生理学
  • 肝臓学
  • 消化器病学
  • 生理学(医学)

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