Verotoxin activates mitogen-activated protein kinase in human peripheral blood monocytes: role in apoptosis and proinflammatory cytokine release

P. Cameron, S.J. Smith, M.A. Giembycz, D. Rotondo, R.J. Plevin

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

In this study, we examined the role of mitogen-activated protein (MAP) kinases in the effects of verotoxins (VTs), from Escherichia coli O157:H7, upon both apoptosis and the release of tumour necrosis factor alpha (TNF-α) and granulocyte–macrophage colony-stimulated factor (GM-CSF) from human monocytes. Both VT1 and VT2 stimulated a weak, transient increase in c-Jun-N-terminal kinase (JNK) activity and a strong activation of both p38 mitogen-activated protein kinase (MAP kinase) and extracellular-regulated kinase (ERK) activity in human monocytes, which was sustained in the case of p38 MAP kinase.
Stimulation of human monocytes with VT2 (100 ng ml−1) did not result in an increase in apoptosis; however, the toxin stimulated the release of both TNF-α and GM-CSF. Pretreatment of human monocytes with the p38 MAP kinase inhibitor SB203580, at concentrations from 100 nm to 10 μm, significantly decreased the VT1- and VT2-induced TNF-α and GM-CSF release from monocytes. In contrast, inhibition of MEK1 with PD98059 only significantly decreased GM-CSF release. Pretreatment of monocytes with SP600125 inhibited both GM-CSF and TNF-α production; however, significant effects upon p38 MAP kinase and ERK activation were observed. Taken together, these results suggest a role for p38 MAP kinase and ERK in cytokine generation in response to the verotoxins. A role for JNK remains undetermined.
Original languageEnglish
Pages (from-to)1320-1330
Number of pages10
JournalBritish Journal of Pharmacology
Volume140
Issue number7
DOIs
Publication statusPublished - 2003

Keywords

  • e. coli O157
  • apoptosis
  • verotoxins
  • c-Jun-N-terminal kinase
  • p38 MAP kinase
  • protein kinase

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