title: 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.
abstract: 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.
authors: Department of Pharmacology and Institute of Gastroenterology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: Ji Hye
authors: JH
authors: Seo
authors: Joo Weon
authors: JW
authors: Lim
authors: Hyeyoung
authors: H
authors: Kim
authors: Kyung Hwan
authors: KH
authors: Kim
mesh_terms: 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
chemical_list: 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