Participation of mitogen-activated protein kinase in thapsigargin- and TPA-induced histamine production in murine macrophage RAW 264.7 cells

Muneshige Shiraishi, Noriyasu Hirasawa, Yuriko Kobayashi, Shinji Oikawa, Akira Murakami, Kazuo Ohuchi

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

1. Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca2+-ATPase inhibitor, induced histamine production in a time- and concentration-dependent manner. 2. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), also enhanced histamine production. 3. α-Fluoromethylhistidine, a suicide substrate of L-histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production. 4. Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. 5. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6. The other MEK-1 inhibitor, U-0126, also inhibited both the thapsigargin- and TPA-induced histamine production in a concentration-dependent manner. 7. Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin- and TPA-induced increases in the HDC mRNA level. 8. These findings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin- and TPA-induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.

Original languageEnglish
Pages (from-to)515-524
Number of pages10
JournalBritish Journal of Pharmacology
Volume129
Issue number3
DOIs
Publication statusPublished - 2000

Keywords

  • Histamine
  • L-histidine decarboxylase
  • Murine macrophage RAW 264.7 cell
  • TPA
  • Thapsigargin
  • p38 MAP kinase
  • p44/p42 MAP kinase

ASJC Scopus subject areas

  • Pharmacology

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