Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling

Pawel Zymek, Deuk Young Nah, Marcin Bujak, Guofeng Ren, Anna Koerting, Thorsten Leucker, Peter Huebener, George Taffet, Mark Entman, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Objective: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. Methods: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10 -/- and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. Results: Infarcted IL-10 -/- mice exhibited comparable mortality rates with WT animals. Although IL-10 -/- mice had higher peak tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-α-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-β1 pre-incubation suppressed interferon-γ-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-α. Conclusions: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.

Original languageEnglish (US)
Pages (from-to)313-322
Number of pages10
JournalCardiovascular Research
Volume74
Issue number2
DOIs
StatePublished - May 1 2007
Externally publishedYes

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Ventricular Remodeling
Interleukin-10
Infarction
Tumor Necrosis Factor-alpha
Fibroblasts
Chemokines
Messenger RNA
Anti-Inflammatory Agents
Chemokine CXCL10
Chemokine CCL2
Transforming Growth Factors
Matrix Metalloproteinases
Genes
Reperfusion
Extracellular Matrix
Myocardium
Neutrophils
Myocardial Infarction
Cytokines
Inflammation

Keywords

  • Cytokines
  • Hispathology
  • Infarction
  • Interleukins
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. / Zymek, Pawel; Nah, Deuk Young; Bujak, Marcin; Ren, Guofeng; Koerting, Anna; Leucker, Thorsten; Huebener, Peter; Taffet, George; Entman, Mark; Frangogiannis, Nikolaos G.

In: Cardiovascular Research, Vol. 74, No. 2, 01.05.2007, p. 313-322.

Research output: Contribution to journalArticle

Zymek, P, Nah, DY, Bujak, M, Ren, G, Koerting, A, Leucker, T, Huebener, P, Taffet, G, Entman, M & Frangogiannis, NG 2007, 'Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling', Cardiovascular Research, vol. 74, no. 2, pp. 313-322. https://doi.org/10.1016/j.cardiores.2006.11.028
Zymek, Pawel ; Nah, Deuk Young ; Bujak, Marcin ; Ren, Guofeng ; Koerting, Anna ; Leucker, Thorsten ; Huebener, Peter ; Taffet, George ; Entman, Mark ; Frangogiannis, Nikolaos G. / Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. In: Cardiovascular Research. 2007 ; Vol. 74, No. 2. pp. 313-322.
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abstract = "Objective: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. Methods: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10 -/- and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. Results: Infarcted IL-10 -/- mice exhibited comparable mortality rates with WT animals. Although IL-10 -/- mice had higher peak tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-α-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-β1 pre-incubation suppressed interferon-γ-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-α. Conclusions: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.",
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T1 - Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling

AU - Zymek, Pawel

AU - Nah, Deuk Young

AU - Bujak, Marcin

AU - Ren, Guofeng

AU - Koerting, Anna

AU - Leucker, Thorsten

AU - Huebener, Peter

AU - Taffet, George

AU - Entman, Mark

AU - Frangogiannis, Nikolaos G.

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Y1 - 2007/5/1

N2 - Objective: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. Methods: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10 -/- and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. Results: Infarcted IL-10 -/- mice exhibited comparable mortality rates with WT animals. Although IL-10 -/- mice had higher peak tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-α-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-β1 pre-incubation suppressed interferon-γ-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-α. Conclusions: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.

AB - Objective: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. Methods: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10 -/- and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. Results: Infarcted IL-10 -/- mice exhibited comparable mortality rates with WT animals. Although IL-10 -/- mice had higher peak tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-α-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-β1 pre-incubation suppressed interferon-γ-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-α. Conclusions: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.

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KW - Hispathology

KW - Infarction

KW - Interleukins

KW - Remodeling

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