title: C-reactive protein elicits white blood cell activation in humans.
abstract: OBJECTIVE
  Consistent epidemiologic evidence suggests that acute infections increase the risk for acute cardiovascular events. We tested in humans whether activation of peripheral leukocytes in reaction to the administration of recombinant human C-reactive protein (rhCRP) may provide a mechanism for infectious diseases to promote atherosclerotic disease.
  
  
  RESULTS
  By using quantitative real-time polymerase chain reaction analysis, whole-blood expression profiles were analyzed for 95 inflammatory markers before and after infusion of 1.25 mg/kg rhCRP in 5 male volunteers. Relevant transcript levels were measured at baseline and 4 and 8 hours after rhCRP-infusion. CRP caused significant up-regulation of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, plasminogen activator urokinase, macrophage inflammatory protein 1 alpha, and nuclear factor of kappa B inhibitor mRNAs in peripheral leukocytes. mRNA up-regulation of MMP-9 and MCP-1 was 17- and 11-fold, respectively. The corresponding increase in plasma protein levels of MMP-9 (78+/-32 ng/mL to 109+/-41 ng/mL; P=.014) and MCP-1 (312+/-92 pg/mL to 2590+/-898 pg/mL; P=.007) closely mirrored mRNA findings. Also, in whole-blood culture stimulation assays, CRP induced proinflammatory changes. Notably, heat inactivation abolished the capacity of CRP to evoke these proinflammatory changes, excluding a role for contaminants within the purified CRP preparation.
  
  
  CONCLUSIONS
  CRP elicits activation of peripheral leukocytes with ensuing secretion of plaque-destabilizing mediators. These findings are consistent with the hypothesis that infectious diseases trigger manifestations of atherosclerosis, in which CRP elevation might contribute to the onset of cardiovascular events.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. r.j.bisoendial@amc.uva.nl
authors.forename: Radjesh J
authors.initials: RJ
authors.lastname: Bisoendial
authors.forename: Rakesh S
authors.initials: RS
authors.lastname: Birjmohun
authors.forename: Fatima
authors.initials: F
authors.lastname: Akdim
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartman
authors.forename: Els R
authors.initials: ER
authors.lastname: de Groot
authors.forename: Danute M
authors.initials: DM
authors.lastname: Bankaitis-Davis
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000378:metabolism*; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007958:Leukocyte Count / Q000379:methods; D007962:Leukocytes / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D002097:C-Reactive Protein; D020780:Matrix Metalloproteinase 9