title: Activation of CXCR2 by extracellular matrix degradation product acetylated Pro-Gly-Pro has therapeutic effects against sepsis.
abstract: BACKGROUND
  Acetylated Pro-Gly-Pro (Ac-PGP) is an endogenous degradation product of extracellular collagen that binds to leukocyte-expressed chemoattractant receptor CXCR2. Although certain agents that block CXCR2-mediated signaling protect against experimental sepsis, the roles of Ac-PGP and CXCR2 in sepsis are unclear.
  
  
  OBJECTIVE
  To investigate the role of Ac-PGP and its receptor, CXCR2, in murine models of cecal ligation and puncture (CLP)-induced polymicrobial sepsis and organ injury.
  
  
  METHODS
  The impact of in vivo Ac-PGP treatment on animal survival after induction of experimental sepsis was assessed. Vital organ inflammation and immune cell apoptosis were evaluated by histology, and the modulation of proinflammatory cytokine production and bactericidal activity by Ac-PGP in mouse and human blood leukocytes was measured.
  
  
  RESULTS
  The activation of CXCR2 by tripeptide agonist Ac-PGP dramatically improved survival in three experimental sepsis models. Ac-PGP elicited bactericidal activity via the generation of hydrogen peroxide, inhibited lung inflammation, and reduced immune cell apoptosis. Fluorescein isothiocyanate-labeled PGP bound directly to CXCR2, and the protective effect of Ac-PGP in sepsis was abolished in CXCR2-deficient mice. Ac-PGP treatment enhanced the production of type 1 cytokines (IFN-γ and IL-12) but inhibited the production of proinflammatory cytokines (tumor necrosis factor [TNF]-α, IL-1β, and IL-6) in vivo. In vitro, Ac-PGP directly increased IFN-γ production and decreased the LPS-stimulated production of TNF-α by mouse splenocytes and human leukocytes. Furthermore, direct treatment of LPS-stimulated splenocytes with IFN-γ resulted in diminished secretion of TNF-α and IL-6.
  
  
  CONCLUSIONS
  CXCR2 and Ac-PGP are thus novel target and starting molecules, respectively, for the development of therapeutic agents against sepsis.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Sang Doo
authors.initials: SD
authors.lastname: Kim
authors.forename: Ha Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Jae Woong
authors.initials: JW
authors.lastname: Shim
authors.forename: Hak Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Joon Seong
authors.initials: JS
authors.lastname: Park
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Baek
authors.forename: Brian A
authors.initials: BA
authors.lastname: Zabel
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000517:prevention & control*
chemical_list: D009842:Oligopeptides; D023063:Receptors, Interleukin-8B; C113164:prolyl-glycyl-proline; D011392:Proline