TNF-α and Heart Failure

Abstract

achexia (from the Greek kakos, meaning bad, and hexis, a state of being) has both fascinated and challenged clini-cians and scientists for many years. It has been known since the earliest descriptions of heart failure that cachexia can be associated with the late stages of the syndrome. Cachectin, a hormone that suppresses the expression of lipoprotein lipase and other anabolic enzymes in fat, was purified in 1985. 1 Tumor necrosis factor (TNF) had been isolated much earlier, in the 1970s. 2 After the purification of cachectin, the complementary DNAs and genes encoding each protein were cloned almost immediately and were shown to be identical. 3 Cachectin and TNF were one and the same. Since then, considerable evidence has accumulated suggesting a role of TNF in various inflammatory conditions, 4 and TNF-is now known to be one of the most pleiotropic of all cytokines. Among a large number of cellular responses to TNF-are immu-noregulation, transcriptional regulation, cytotoxicity, and antiviral activity. 5 Two distinct TNF-receptors occur on multiple cell surfaces: a 55-kDa (TNF-R1) and a 75-kDa (TNF-R2) protein, with the TNF-R1 receptor subserving most of the activity of TNF, including cytotoxicity, fibroblast proliferation, bacterial resistance, prostaglandin E 2 synthesis, antiviral activity, and induction of superoxide dismutase. 5 The TNF-R2 receptor subserves T-cell proliferation, dermal necrosis, and insulin resistance, although there are overlapping activities between TNF-R1 and TNF-R2. The cytoplasmic domains of the 2 receptors are structurally different, suggesting distinctive evolutionary signal transduction pathways.