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Haskó, G. et al.

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)-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.[1]

References

Poly(ADP-ribose) polymerase is a regulator of chemokine production: relevance for the pathogenesis of shock and inflammation. Haskó, G., Mabley, J.G., Németh, Z.H., Pacher, P., Deitch, E.A., Szabó, C. Mol. Med. (2002) [Pubmed]

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