Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-kappaB and induces chemokine expression in gastric epithelial AGS cells.
Oxidant-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) have been considered as the regulators of inducible genes such as chemokines. Since oxygen radicals are considered as an important regulator in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastric ulceration and carcinogenesis, chemokines such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) may be regulated by NF-kappaB and/or AP-1. Ras, the upstream activator for mitogen-activated protein kinase (MAPK) and MAPK cascade regulate AP-1 activation. The present study aims to investigate whether H. pylori in a Korean isolate (HP99) induces the expression of chemokines (IL-8, MCP-1), which is regulated by Ras, MAPK, AP-1, and NF-kappaB in gastric epithelial AGS cells, and whether these transcriptional regulations of chemokines are inhibited by transfection with mutant genes for Ras (ras N-17), c-Jun (TAM-67), and IkappaBalpha (MAD-3) or treatment with MAPK inhibitors (U0126 for extracellular signal-regulated kinase or SB203580 for p38 kinase). In addition, virulence factors of HP99 were characterized by PCR analysis for the isolated DNA. As a result, HP99 is identified as cagA+, vacA s1b, m2, iceA1 H. pylori strain. HP99 induced a time-dependent expression of mRNA and protein for IL-8 and MCP-1 via mediation of MAPK, AP-1, and NF-kappaB. Transfection with mutant genes for Ras, c-Jun, and IkappaBalpha and treatment with MAPK inhibitors suppressed H. pylori-induced activation of transcription factors (NF-kappaB, AP-1) and expression of chemokines (IL-8, MCP-1) in AGS cells. In conclusion, Ras and MAPK cascade may act as the upstream signaling for the activation of AP-1 and NF-kappaB, which induce chemokine expression in H. pylori-infected AGS cells. Specific targeting of the activation of NF-kappaB and AP-1 may be effective for the prevention or treatment of gastric inflammation associated with H. pylori infection.
Seo
Ji Hye
JH
Department of Pharmacology and Institute of Gastroenterology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Lim
Joo Weon
JW
Kim
Hyeyoung
H
Kim
Kyung Hwan
KH
D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004269:DNA, Bacterial / Q000032:analysis / Q000235:genetics; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D015964:Gene Expression Regulation, Bacterial; D016481:Helicobacter Infections / Q000473:pathology / Q000503:physiopathology; D016480:Helicobacter pylori / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D037521:Virulence Factors / Q000235:genetics
D018932:Chemokine CCL2; D004269:DNA, Bacterial; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D037521:Virulence Factors; D020928:Mitogen-Activated Protein Kinases