{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:44:56Z","timestamp":1790297096937,"version":"4.1.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2008,4,1]],"date-time":"2008-04-01T00:00:00Z","timestamp":1207008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Helicobacter pylori VacA induces multiple effects on susceptible cells, including vacuolation, mitochondrial damage, inhibition of cell growth, and enhanced cyclooxygenase-2 expression. To assess the ability of H. pylori to modulate the production of inflammatory mediators, we examined the mechanisms by which VacA enhanced IL-8 production by promonocytic U937 cells, which demonstrated the greatest VacA-induced IL-8 release of the cells tested. Inhibitors of p38 MAPK (SB203580), ERK1\/2 (PD98059), I\u03baB\u03b1 ((E)-3-(4-methylphenylsulfonyl)-2-propenenitrile), Ca2+ entry (SKF96365), and intracellular Ca2+ channels (dantrolene) blocked VacA-induced IL-8 production. Furthermore, an intracellular Ca2+ chelator (BAPTA-AM), which inhibited VacA-activated p38 MAPK, caused a dose-dependent reduction in VacA-induced IL-8 secretion by U937 cells, implying a role for intracellular Ca2+ in mediating activation of MAPK and the canonical NF-\u03baB pathway. VacA stimulated translocation of NF-\u03baBp65 to the nucleus, consistent with enhancement of IL-8 expression by activation of the NF-\u03baB pathway. In addition, small interfering RNA of activating transcription factor (ATF)-2 or CREB, which is a p38MAPK substrate and binds to the AP-1 site of the IL-8 promoter, inhibited VacA-induced IL-8 production. VacA activated an IL-8 promoter containing an NF-IL-6 site, but not a mutated AP-1 or NF-\u03baB site, suggesting direct involvement of the ATF-2\/CREB binding region or NF-\u03baB-binding regions in VacA-induced IL-8 promoter activation. Thus, in U937 cells, VacA directly increases IL-8 production by activation of the p38 MAPK via intracellular Ca2+ release, leading to activation of the transcription factors, ATF-2, CREB, and NF-\u03baB.<\/jats:p>","DOI":"10.4049\/jimmunol.180.7.5017","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:11:22Z","timestamp":1397862682000},"page":"5017-5027","source":"Crossref","is-referenced-by-count":78,"title":["Molecular Characterization of <i>Helicobacter pylori<\/i> VacA Induction of IL-8 in U937 Cells Reveals a Prominent Role for p38MAPK in Activating Transcription Factor-2, cAMP Response Element Binding Protein, and NF-\u03baB Activation"],"prefix":"10.1093","volume":"180","author":[{"given":"Junzo","family":"Hisatsune","sequence":"first","affiliation":[{"name":"Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University , Nagasaki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University , Nagasaki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Isomoto","sequence":"additional","affiliation":[{"name":"Department of Endoscopy, Nagasaki University School of Medicine , Nagasaki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Kurazono","sequence":"additional","affiliation":[{"name":"Department of Applied Veterinary Medicine and Public Health, Obihiro University of Agriculture and Veterinary Medicine , Obihiro ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Mukaida","sequence":"additional","affiliation":[{"name":"Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University , Kanazawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asish K","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University , Nagasaki ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Azuma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kobe University School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Yamaoka","sequence":"additional","affiliation":[{"name":"Department of Medicine-Gastroenterology, Michael E. 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