title: Roles of reactive oxygen species in CXCL8 and CCL2 expression in response to the 30-kDa antigen of Mycobacterium tuberculosis.
abstract: BACKGROUND
  The 30-kDa antigen (Ag) of Mycobacterium tuberculosis (M. tuberculosis) is a strong inducer of innate and adaptive immune responses in human tuberculosis. The generation of reactive oxygen species (ROS) plays an important role in inflammatory signaling as well as antimicrobial defense.
  
  
  METHODS
  In this study, we investigated the role of ROS in the activation of mitogen-activated protein kinases (MAPKs) and secretion of the CXC chemokine ligand 8 (CXCL8) and CC chemokine ligand 2 (CCL2) by human monocytes stimulated with the 30-kDa Ag of M. tuberculosis H37Rv.
  
  
  RESULTS
  Treatment of human monocytes with the 30-kDa Ag activated rapid superoxide generation. In addition, the 30-kDa Ag activated mRNA and protein expression of CXCL8 and CCL2 in human primary monocytes through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent ROS generation. Analysis of MAPK activation (extracellular signal-regulated kinase (ERK) 1/2 and p38) showed rapid phosphorylation of both subfamilies in response to the 30-kDa Ag. In addition, 30-kDa-induced MAPK activation was inhibited in a dose-dependent manner by pretreatment with ROS scavengers. Toll-like receptor (TLR) 2 was required for ROS generation, chemokine production, and MAPK activation following stimulation with the 30-kDa Ag. Using highly specific signaling pathway inhibitors, we found that both p38 and ERK1/2 activation are essential for 30-kDa Ag-induced CCL2 but not CXCL8 production in human monocytes.
  
  
  CONCLUSIONS
  These results indicate that TLR2-ROS signaling plays a crucial role in the 30-kDa Ag-mediated expression of CXCL8 and CCL2 in human monocytes. In addition, both p38 and ERK1/2 activation are essential for 30-kDa Ag-stimulated CCL2 production by monocytes.
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-ku, Daejeon, 301-747, South Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Kwang-Kyu
authors.initials: KK
authors.lastname: Kim
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Lee
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Paik
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases