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In endothelial cells, at least three independent pathways regulate MCP-1 expression by NF-\u03baB and AP-1.<jats:italic>Orientia tsutsugamushi<\/jats:italic>causes vasculitis in humans by replicating inside macrophages and endothelial cells. In the present study, we investigated the<jats:italic>cis<\/jats:italic>-acting and<jats:italic>trans<\/jats:italic>-acting elements involved in<jats:italic>O. tsutsugamushi<\/jats:italic>-induced MCP-1 gene expression in human umbilical vein endothelial cells (HUVEC). Although NF-\u03baB activation was observed in HUVEC infected with<jats:italic>O. tsutsugamushi<\/jats:italic>, inhibition of NF-\u03baB activation did not affect the MCP-1 expression. However, treatment of HUVEC with extracellular signal-regulated kinase (ERK) kinase inhibitor or p38 mitogen-activated protein kinase (MAPK) inhibitor suppressed expression of MCP-1 mRNA concomitant with downregulation of activator protein 1 (AP-1) activation. Deletion of triphorbol acetate response elements (TRE) at position \u221269 to \u221263 of MCP-1 gene abolished inducible promoter activity. Deletion of TRE at position \u221269 to \u221263\u221296 to \u221290 or deletion of NF-\u03baB-binding site at position \u221269 to \u221263\u221288 to \u221279 did not affect the inducibility of promoter. Site-directed mutagenesis of the NF-\u03baB binding sites at positions \u22122640 to \u22122632, \u22122612 to \u22122603 in the enhancer region, or the AP-1 biding site at position \u22122276 to \u22122270 decreased the inducible activity of the promoter. Taken together, AP-1 activation by both the ERK pathway and the p38 MAPK pathway as well as their binding to TRE at position \u221269 to \u221263 in proximal promoter and TRE at position \u22122276 to \u22122270 in enhancer region is altogether essential in induction of MCP-1 mRNA in HUVEC infected with<jats:italic>O. tsutsugamushi<\/jats:italic>. Although NF-\u03baB activation is not essential per se, the \u03baB site in the enhancer region is important in MCP-1 induction of HUVEC. This discrepancy in the involvement of the NF-\u03baB may be due to the function of chromatin structures and other transcription cofactors in the regulation of MCP-1 gene expression in response to<jats:italic>O. tsutsugamushi<\/jats:italic>infectioin.<\/jats:p>","DOI":"10.1128\/iai.70.9.4841-4850.2002","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T19:36:19Z","timestamp":1033500979000},"page":"4841-4850","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":50,"title":["Induction of the Gene Encoding Macrophage Chemoattractant Protein 1 by<i>Orientia tsutsugamushi<\/i>in Human Endothelial Cells Involves Activation of Transcription Factor Activator Protein 1"],"prefix":"10.1128","volume":"70","author":[{"given":"Nam-Hyuk","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Yong","family":"Seong","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung-Sook","family":"Huh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na-Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung-sik","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ik-sang","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine, and Institute of Endemic Disease, Seoul National University Medical Research Center, Chongno-gu, Seoul 110-799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"603","volume":"21","year":"1945","unstructured":"Allen, A. 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