Poly(ADP-ribose) polymerase is a regulator of chemokine production

Relevance for the pathogenesis of shock and inflammation

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)283-289
Number of pages7
JournalMolecular Medicine
Volume8
Issue number5
StatePublished - 2002
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Chemokines
Shock
Inflammation
Chemokine CXCL2
Macrophage Inflammatory Proteins
Dextran Sulfate
Enzyme Activation
Neutrophil Infiltration
Colitis
Septic Shock
Reperfusion Injury
Signal Transduction
Protein Isoforms
Leukocytes
Anti-Inflammatory Agents
Transcription Factors
Up-Regulation
Fibroblasts
Macrophages

ASJC Scopus subject areas

  • Genetics

Cite this

Poly(ADP-ribose) polymerase is a regulator of chemokine production : Relevance for the pathogenesis of shock and inflammation. / Haskó, György; Mabley, Jon G.; Németh, Zoltán H.; Pacher, Pál; Deitch, Edwin A.; Szabo, Csaba.

In: Molecular Medicine, Vol. 8, No. 5, 2002, p. 283-289.

Research output: Contribution to journalArticle

Haskó, György ; Mabley, Jon G. ; Németh, Zoltán H. ; Pacher, Pál ; Deitch, Edwin A. ; Szabo, Csaba. / Poly(ADP-ribose) polymerase is a regulator of chemokine production : Relevance for the pathogenesis of shock and inflammation. In: Molecular Medicine. 2002 ; Vol. 8, No. 5. pp. 283-289.
@article{27d77e3e7b5c4047abbf3bc03cf0b7f0,
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. 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.",
author = "Gy{\"o}rgy Hask{\'o} and Mabley, {Jon G.} and N{\'e}meth, {Zolt{\'a}n H.} and P{\'a}l Pacher and Deitch, {Edwin A.} and Csaba Szabo",
year = "2002",
language = "English (US)",
volume = "8",
pages = "283--289",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",
number = "5",

}

TY - JOUR

T1 - Poly(ADP-ribose) polymerase is a regulator of chemokine production

T2 - Relevance for the pathogenesis of shock and inflammation

AU - Haskó, György

AU - Mabley, Jon G.

AU - Németh, Zoltán H.

AU - Pacher, Pál

AU - Deitch, Edwin A.

AU - Szabo, Csaba

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0036391974&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036391974&partnerID=8YFLogxK

M3 - Article

VL - 8

SP - 283

EP - 289

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

IS - 5

ER -