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

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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.

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.

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Acknowledgments

We are grateful for the research support of the National Institutes of Health (R01GM60915 and R01GM66189) to C.S. and G.H. respectively.

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Authors and Affiliations

  1. Inotek Pharmaceuticals Corporation, Suite 419E, 100 Cummings Ctr., Beverly, Massachusetts, 01915, USA

    György Haskó, Jon G. Mabley, Pál Pacher & Csaba Szabó

  2. Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey, USA

    György Haskó, Zoltán H. Németh, Edwin A. Deitch & Csaba Szabó

Authors
  1. György Haskó
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  2. Jon G. Mabley
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  3. Zoltán H. Németh
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  4. Pál Pacher
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  5. Edwin A. Deitch
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  6. Csaba Szabó
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Correspondence to Csaba Szabó.

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Contributed by: C. Szabó.

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Haskó, G., Mabley, J.G., Németh, Z.H. et al. Poly(ADP-ribose) Polymerase is a Regulator of Chemokine Production: Relevance for the Pathogenesis of Shock and Inflammation. Mol Med 8, 283–289 (2002). https://doi.org/10.1007/BF03402154

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