Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion

Nikolaos G. Frangogiannis, Merry L. Lindsey, Lloyd H. Michael, Keith A. Youker, Robert B. Bressler, Leonardo H. Mendoza, Robert N. Spengler, C. Wayne Smith, Mark L. Entman

Research output: Contribution to journalArticlepeer-review

449 Scopus citations


Background - Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1- CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. Methods and Results - Constitutive expression of TNF-α and not IL-1β was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-α in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-α in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-α. Conclusions - Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-α. We suggest that mast cell-derived TNF-α may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil- induced injury.

Original languageEnglish (US)
Pages (from-to)699-710
Number of pages12
Issue number7
StatePublished - Aug 18 1998
Externally publishedYes


  • Cells
  • Cytokines
  • Ischemia
  • Myocardial infarction
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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