Regulation of myocardial stromal cell–derived factor 1α/CXCL12 by tumor necrosis factor signaling

Meijing Wang, Lina Wang, Chunyan Huang, I-Wen Wang, Mark Turrentine

Research output: Contribution to journalArticle

Abstract

Background Global myocardial ischemia–reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor α (TNF) instantly and upregulated expression of stromal cell–derived factor 1 α (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF-1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR-initiated actions. Methods Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription–polymerase chain reaction. Protein kinases of IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α) and c-jun N-terminal kinase were also determined using Western blot assay. Results TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IκB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. Conclusions Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling-initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments.

Original languageEnglish (US)
Pages (from-to)155-163
Number of pages9
JournalJournal of Surgical Research
Volume207
DOIs
StatePublished - Jan 1 2017

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Tumor Necrosis Factor-alpha
Tumor Necrosis Factor Receptors
Receptors, Tumor Necrosis Factor, Type II
Small Interfering RNA
Down-Regulation
Heart Injuries
Heart Neoplasms
JNK Mitogen-Activated Protein Kinases
Chemokines
Protein Kinases
Genes
Myocardial Ischemia
Transfection
Myocardium
B-Lymphocytes
Endothelial Cells
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cytokines
Light

Keywords

  • CXCL12
  • Myocardial ischemia
  • Myocardial SDF-1
  • TNF receptor
  • TNF signaling

ASJC Scopus subject areas

  • Surgery

Cite this

Regulation of myocardial stromal cell–derived factor 1α/CXCL12 by tumor necrosis factor signaling. / Wang, Meijing; Wang, Lina; Huang, Chunyan; Wang, I-Wen; Turrentine, Mark.

In: Journal of Surgical Research, Vol. 207, 01.01.2017, p. 155-163.

Research output: Contribution to journalArticle

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title = "Regulation of myocardial stromal cell–derived factor 1α/CXCL12 by tumor necrosis factor signaling",
abstract = "Background Global myocardial ischemia–reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor α (TNF) instantly and upregulated expression of stromal cell–derived factor 1 α (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF-1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR-initiated actions. Methods Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription–polymerase chain reaction. Protein kinases of IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α) and c-jun N-terminal kinase were also determined using Western blot assay. Results TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IκB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. Conclusions Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling-initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments.",
keywords = "CXCL12, Myocardial ischemia, Myocardial SDF-1, TNF receptor, TNF signaling",
author = "Meijing Wang and Lina Wang and Chunyan Huang and I-Wen Wang and Mark Turrentine",
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T1 - Regulation of myocardial stromal cell–derived factor 1α/CXCL12 by tumor necrosis factor signaling

AU - Wang, Meijing

AU - Wang, Lina

AU - Huang, Chunyan

AU - Wang, I-Wen

AU - Turrentine, Mark

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background Global myocardial ischemia–reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor α (TNF) instantly and upregulated expression of stromal cell–derived factor 1 α (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF-1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR-initiated actions. Methods Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription–polymerase chain reaction. Protein kinases of IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α) and c-jun N-terminal kinase were also determined using Western blot assay. Results TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IκB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. Conclusions Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling-initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments.

AB - Background Global myocardial ischemia–reperfusion (I/R) occurs during cardiac operations. This I/R injury leads to increased production of tumor necrosis factor α (TNF) instantly and upregulated expression of stromal cell–derived factor 1 α (SDF-1). On the basis of the published data from our laboratory and other groups, locally produced TNF contributes to cardiac dysfunction mainly via binding to its receptor (tumor necrosis factor receptor 1 [TNFR1]), whereas ischemia-induced myocardial SDF-1 mediates cardioprotection. Although TNF has been shown to work as an upstream initiator for induction of other cytokines and chemokines, there is no information regarding the interaction among TNF, TNFRs, and myocardial SDF-1 expression. In this study, given that TNF downregulated SDF-1 in vascular endothelial cells, we therefore hypothesized that TNF would have a negative effect on myocardial SDF-1 production, which is attributable to TNFR-initiated actions. Methods Using a Langendorff model, isolated male mouse hearts were infused with TNF for 45 min. Male adult mouse hearts from wild type, TNFR1 knockout (TNFR1KO), TNFR2KO, and TNFR1/2KO were subjected to global I/R. H9c2 cells with small interfering RNA transfection were used as an in vitro model. The levels of SDF-1 (protein and messenger RNA) were detected by enzyme-linked immunosorbent assay and quantitative reverse transcription–polymerase chain reaction. Protein kinases of IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α) and c-jun N-terminal kinase were also determined using Western blot assay. Results TNF infusion downregulated myocardial SDF-1 production in a dose-dependent manner in the hearts. In addition, using TNF significantly decreased SDF-1 expression in cardiomyoblasts (H9c2 cells), which was associated with reduced IκB level. Knockdown of TNFR1 or TNFR2 by small interfering RNAs neutralized TNF-suppressed SDF-1 in H9c2 cells. Furthermore, deletion of TNFR1/2 or TNFR2 increased SDF-1 production in the hearts after I/R. Conclusions Our study represents the initial evidence showing that TNF plays an inhibitory role in modulating myocardial SDF-1 production and blockade of TNF signaling by ablation of TNFR1 and TNFR2 genes increased SDF-1 expression in the heart. These data expand on TNF signaling-initiated mechanisms in myocardium, which may lend a more complete understanding of SDF-1 and TNFR-derived actions in hopes of advancing ischemic heart injury treatments.

KW - CXCL12

KW - Myocardial ischemia

KW - Myocardial SDF-1

KW - TNF receptor

KW - TNF signaling

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