title: Regulation of myocardial stromal cell-derived factor 1α/CXCL12 by tumor necrosis factor signaling.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: meiwang@iupui.edu.
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: I-Wen
authors.initials: IW
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Turrentine
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D054377:Chemokine CXCL12; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: CXCL12; Myocardial SDF-1; Myocardial ischemia; TNF receptor; TNF signaling