title: Poly(ADP-ribose) polymerase is a regulator of chemokine production: relevance for the pathogenesis of shock and inflammation.
abstract: BACKGROUND
  Chemokines are key regulators of leukocyte traffic in various forms of inflammation and reperfusion injury. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) importantly contributes to the up-regulation of a variety of proinflammatory signal transduction pathways and associated genes.
  
  
  METHODS
  We tested whether the expression of the chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-2 are under the control of PARP during inflammation.
  
  
  RESULTS
  Pharmacologic inhibition of PARP and genetic deletion of PARP suppressed the expression of MIP-1a and MIP-2 protein and mRNA in immunostimulated cultured murine macrophages and fibroblasts. PARP inhibition also suppressed the activation of NF-kappaB, a key transcription factor known to be involved in the generation of chemokines in immunostimulated cells. In vivo, in various models of local and systemic inflammation, including dextran sodium sulfate-induced colitis and endotoxic shock, pharmacologic inhibition of PARP suppressed the expression of MIP-1alpha and MIP-2. These effects were associated with a marked suppression of the inflammatory response, including an attenuation of neutrophil infiltration into inflamed organs.
  
  
  CONCLUSIONS
  A combination approach of pharmacologic inhibition and genetic deletion revealed that the major isoform of PARP (PARP-1) plays a predominant, but not exclusive, role in the regulation of chemokine production in vivo. Suppression of chemokine expression may be a novel mode of anti-inflammatory action of PARP inhibition.
mesh_terms: D000818:Animals; D018925:Chemokines / Q000096:biosynthesis* / Q000378:metabolism; D003092:Colitis / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012769:Shock / Q000209:etiology*
chemical_list: D018925:Chemokines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases