Poly(ADP-ribose) polymerase is a regulator of chemokine production: Relevance for the pathogenesis of shock and inflammation

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. Materials and Methods: We tested whether the expression of the chemokines macrophage inflammatory protein (MIP)-1α 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-1α and MIP-2 protein and mRNA in immunostimulated cultured murine macrophages and fibroblasts. PARP inhibition also suppressed the activation of NF-κB, 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-1α 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.