Tumor Necrosis Factor-α and Its Receptors 1 and 2

In healthy hearts, tumor necrosis factor-α (TNF-α) concentration is low, and TNF-α is mainly located in endothelium and resident mast cells.1 TNF-α receptors (TNFRs) 1 (TNFR1) and 2 (TNFR2) are expressed on most cardiac cells, including cardiomyocytes.2 During myocardial ischemia, preformed TNF-α is released within minutes from resident mast cells and macrophages.3 With persistent ischemia, TNF-α also originates from cardiomyocytes.4 In rats after myocardial infarction (MI), TNFR1 density is increased for 10 days, whereas TNFR2 density remains unchanged.5 In contrast, TNFR1 and TNFR2 are both downregulated in the failing heart, whereas soluble TNFRs are increased6 owing to proteolytic cleavage of cardiomyocyte TNFR and release from circulating exosome-like vesicles.7 Increased soluble TNFRs decrease TNF-α bioactivity while at the same time prolonging its half-life.8 Article p 1386 TNF-α contributes to both reversible (contractile dysfunction4,9) and irreversible (MI) injury.1 Preischemic treatment with TNF-α antibodies10 or soluble TNFR1,11 permanent TNF-α knockout,12 or knockout of TNFR1 but not TNFR213 all reduce infarct size. The latter finding highlights the functional difference of TNFR1 and TNFR2 activation for ischemia/reperfusion injury: Only TNFR1 signaling is detrimental (Figure). Figure. Signaling cascade activated (→) or inhibited (⊣) by TNFR1 (red) or TNFR2 (blue) activation. sTNFR1 indicates soluble TNFR1; sTNFR2, soluble TNFR2; S1-P, sphingosine-1-phosphate; NF-κB, nuclear factor-κB; SOCS3, suppressor of cytokine signaling 3; ROS, reactive oxygen species; Akt-P, phosphorylated Akt, a homologue of the transforming v-Akt; NADPH-Ox, NADPH oxidase; STAT3-P, phosphorylated signal transducer and activator of transcription; Jnk-P, phosphorylated c-jun N-terminal kinase; p38-P, phosphorylated mitogen-activated protein kinase; Erk-P, phosphorylated extracellular signal-regulated kinase; PKC, protein kinase C; CamK, calcium/calmodulin-dependent kinase; MMP-2/9, matrix metalloproteinases 2 and 9; and IL-6, interleukin 6. Red indicates proteins involved in apoptosis; purple, proteins involved in growth; green, …