title: Novel regulatory mechanism and functional implication of plasminogen activator inhibitor-1 (PAI-1) expression in CpG-ODN-stimulated macrophages.
abstract: Macrophages are activated by recognizing bacterial DNA and CpG-oligodeoxynucleotides (CpG-ODNs) through Toll-like receptor-9 (TLR-9). Plasminogen activator inhibitor-1 (PAI-1) has been shown to be an important factor in inflammation-induced macrophage migration which is essential for defense functions. The aim of this study was to demonstrate the molecular mechanism associated with the regulation of PAI-1 expression and its biological significance in CpG-ODN-stimulated mouse macrophages. Our results clearly show that PAI-1 expression in macrophages was highly up-regulated by CpG-ODN-stimulation in vitro and in vivo. The TLR-9-mediated stimulation of PAI-1 expression was independent of the NF-κB pathway and involved the synergistic activation of Sp1 and Elk-1 by the MEK1/2-ERK and JNK signaling pathways. The elevated PAI-1 expression resulted in significantly enhanced transmigration of RAW264.7 cells through vitronectin but not through fibronectin. We suggest that CpG-ODN plays a role in regulating macrophage migration by stimulating the expression of PAI-1, and the migration is modulated depending on the microenvironmental extracellular matrix components.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong, Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
authors.forename: Bikash
authors.initials: B
authors.lastname: Thapa
authors.forename: Yeon Hyang
authors.initials: YH
authors.lastname: Kim
authors.forename: Hyung-Joo
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D060833:Cellular Microenvironment; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D058258:Serpin E2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D015854:Up-Regulation; D019096:Vitronectin / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; C494113:Elk1 protein, mouse; D005353:Fibronectins; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019096:Vitronectin; D050807:ets-Domain Protein Elk-1; D011494:Protein Kinases; C065999:Sp1 kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse