RGD Reference Report - Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury. - Rat Genome Database

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Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury.

Authors: Venkatachalam, K  Prabhu, SD  Reddy, VS  Boylston, WH  Valente, AJ  Chandrasekar, B 
Citation: Venkatachalam K, etal., J Biol Chem. 2009 Mar 20;284(12):7853-65. Epub 2009 Jan 21.
RGD ID: 4889578
Pubmed: PMID:19164288   (View Abstract at PubMed)
PMCID: PMC2658078   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M808824200   (Journal Full-text)

Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-alpha each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/R also induces IL-18 expression and thus exacerbates inflammation and tissue damage. Neutralization of IL-18 signaling should therefore diminish tissue injury following I/R. I/R studies were performed using a chronically instrumented closed chest mouse model. Male C57BL/6 mice underwent 30 min of ischemia by LAD coronary artery ligation followed by various periods of reperfusion. Sham-operated or ischemia-only mice served as controls. A subset of animals was treated with IL-18-neutralizing antibodies 1 h prior to LAD ligation. Ischemic LV tissue was used for analysis. Our results demonstrate that, compared with sham operation and ischemia alone, I/R significantly increased (i) oxidative stress (increased MDA/4-HNE levels), (ii) neutrophil infiltration (increased MPO activity), (iii) NF-kappaB DNA binding activity (p50, p65), and (iv) increased expression of IL-18Rbeta, but not IL-18Ralpha or IL-18BP transcripts. Administration of IL-18-neutralizing antibodies significantly reduced I/R injury measured by reduced infarct size (versus control IgG). In isolated adult mouse cardiomyocytes, simulated ischemia/reperfusion enhanced oxidative stress and biologically active IL-18 expression via IKK-dependent NF-kappaB activation. These results indicate that IL-18 plays a critical role in I/R injury and thus represents a promising therapeutic target.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Il18  (interleukin 18)
Il18bp  (interleukin 18 binding protein)
Il18rap  (interleukin 18 receptor accessory protein)

Genes (Mus musculus)
Il18  (interleukin 18)
Il18bp  (interleukin 18 binding protein)
Il18rap  (interleukin 18 receptor accessory protein)

Genes (Homo sapiens)
IL18  (interleukin 18)
IL18BP  (interleukin 18 binding protein)
IL18RAP  (interleukin 18 receptor accessory protein)


Additional Information