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Verotoxin activates mitogen‐activated protein kinase in human peripheral blood monocytes: role in apoptosis and proinflammatory cytokine release
Author(s) -
Cameron Pamela,
Smith Susan J,
Giembycz Mark A,
Rotondo Dino,
Plevin Robin
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705560
Subject(s) - mitogen activated protein kinase , p38 mitogen activated protein kinases , mitogen activated protein kinase kinase , kinase , monocyte , ask1 , map kinase kinase kinase , mapk/erk pathway , biology , protein kinase a , tumor necrosis factor alpha , proinflammatory cytokine , microbiology and biotechnology , chemistry , endocrinology , immunology , inflammation
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 n M to 10 μ M , 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.British Journal of Pharmacology (2003) 140 , 1320–1330. doi: 10.1038/sj.bjp.0705560