Gastric infection, as well as inflammation, caused by Helicobacter pylori, activates the production of cytokines and chemokines by mononuclear cells; interleukin-8 (IL-8) is one of the major inflammatory chemokines. Since H. pylori does not invade mucosal tissue, we observed the effect of the water extract of H. pylori (HPE), containing shed factors, on the production of IL-8 by human peripheral blood monocytes and the human monocyte cell line THP-1. HPE-treatment induced activation of the mitogen-activated protein kinases (MAPKs) ERK (extracellular signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase), an effect which was not dependent on the presence of the cag pathogenicity island. p38 MAPK activation was sustained. The specific inhibitors, U0126 (for ERK1/2 signalling) and SB203580 (for p38 MAPK signalling), both abrogated IL-8 secretion from HPE-treated THP-1. Dominant-negative mutants of the upstream kinases MEK1 (MAPK/ERK kinase 1), MKK (MAPK kinase) 6 and MKK7 also inhibited IL-8 secretion, pointing to a role of all three MAPKs in HPE-mediated IL-8 release. The inhibitory effects of polymyxin B and anti-CD14 antibody suggested that the effect of HPE on MAPKs was mediated by H. pylori lipopolysaccharide (LPS). By analysis of IL-8-promoter-driven luciferase gene expression, we observed that the effects of HPE-induced nuclear factor-κB (NF-κB) activation and MAPK signalling were mediated at the level of the IL-8 promoter. While ERK1/2 activation could be linked to enhanced DNA binding of activator protein-1 (AP-1), p38 MAPK signalling did not affect AP-1 DNA binding. Taken together, these results provide the first evidence that LPS from H. pylori stimulates IL-8 release from cells of the monocytic lineage through activation of NF-κB and signalling along MAPK cascades. The stimulation of MAPK signalling in macrophages by LPS of H. pylori amplifies the inflammatory response associated with gastric H. pylori infection and needs to be taken into consideration when developing therapeutics based on these signalling pathways.
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November 2002
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Research Article|
November 15 2002
Mitogen-activated protein kinases and nuclear factor-κB regulate Helicobacter pylori-mediated interleukin-8 release from macrophages Available to Purchase
Asima BHATTACHARYYA;
Asima BHATTACHARYYA
∗Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India,
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Shresh PATHAK;
Shresh PATHAK
∗Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India,
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Simanti DATTA;
Simanti DATTA
†National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme XM, Beleghata, Kolkata 700010, India
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Santanu CHATTOPADHYAY;
Santanu CHATTOPADHYAY
†National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme XM, Beleghata, Kolkata 700010, India
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Joyoti BASU;
Joyoti BASU
∗Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India,
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Manikuntala KUNDU
Manikuntala KUNDU
1
∗Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India,
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
April 09 2002
Revision Received:
July 23 2002
Accepted:
August 01 2002
Accepted Manuscript online:
August 01 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 368 (1): 121–129.
Article history
Received:
April 09 2002
Revision Received:
July 23 2002
Accepted:
August 01 2002
Accepted Manuscript online:
August 01 2002
Citation
Asima BHATTACHARYYA, Shresh PATHAK, Simanti DATTA, Santanu CHATTOPADHYAY, Joyoti BASU, Manikuntala KUNDU; Mitogen-activated protein kinases and nuclear factor-κB regulate Helicobacter pylori-mediated interleukin-8 release from macrophages. Biochem J 15 November 2002; 368 (1): 121–129. doi: https://doi.org/10.1042/bj20020555
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