Poly(ADP-ribose) Polymerase is a Regulator of Chemokine Production: Relevance for the Pathogenesis of Shock and Inflammation

Poly(ADP-ribose) Polymerase is a Regulator of Chemokine Production: Relevance for the Pathogenesis of Shock and Inflammation

Molecular Medicine, May 2002

12359959

György Haskó, Jon G. Mabley, Zoltán H. Németh, Pál Pacher, Edwin A. Deitch, Csaba Szabó

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. We tested whether the expression of the chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-2 are under the control of PARP during inflammation. 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. 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.