Cachectin/Tumor Necrosis Factor Exerts Endocrine, Paracrine, and Autocrine Control of Inflammatory Responses

ARASITIC, bacterial, and viral infections and neoplastic disease profoundly affect host metabolism, disrupting normal homeostatic mechanisms both locally and systemically. A large body of research has documented that many of the observed biological responses to invasive stimuli are mediated by host-secreted cytokines, in particular, the secretory products of activated macrophages. One such cytokine, cachectin/tumor necrosis factor (TNF),~ has emerged as a particularly important mediator of inflammatory responses. Among its pleiotropic effects, cachectin/TNF has been shown to play a major endocrine role in the pathogenesis of gram-negative endotoxic shock (14, 118) and to induce catabolic responses which could contribute to the profound wasting (cachexia) associated with many chronic diseases (24, 83, 104, 121). It has been implicated in a variety of disease states including meningococcal septicemia (126), cerebral malaria (43), graft vs. host disease (93), and cancer cachexia (2, 8). Systemic exposure to this potent mediator might elicit the pathologic and catabolic derangements associated with such disease states. Cachectin/TNF has also been shown to exert local, tissuespecific effects. Its wide range of bioactivities includes stimulation of collagenase activity and prostaglandin E2 production by synovial cells (33), stimulation of osteoclast activity and bone resorption (9), promotion of angiogenesis (41, 60), and stimulation of procoagulant and platelet-activating factor activity in endothelial tissue (19, 75). It has also been shown to stimulate proliferation of normal fibroblasts (40, 114, 125), and to induce the release of certain growth factors including interleukin 1 (IL- 1), granulocyte-macrophage colony-stimulating factor (GM-CSF), I]2-interferon, and platelet-derived growth factor (46, 55, 58, 73). The ability of cachectin/TNF to modulate such activities raises the intriguing possibility that it may play a paracrine role in the regulation of normal tissue homeostasis. Cachectin/TNF also exerts profound effects on its own principal cell of origin, the macrophage. It serves as an autocrine immunomodulator, activating macrophages and enhancing their cytotoxic potential in vitro (92). It has been shown to be chemotactic for monocytes, suggesting that its production at a site of injury might function both to recruit additional macrophages and to activate those macrophages already present. 1. Abbreviations used in this paper: IL-1, interleukin 1; LPL, lipoprotein lipase; LPS, lipopolysaccharide; TNF, tumor necrosis factor. The capacity of this potent cytokine to mediate the inflammatory response, to modulate the metabolic activities of diverse tissues, and to augment the function of other cytokines necessitates that its synthesis and release be closely controlled in vivo. Local production of cachectin/TNF at a site of injury might act to limit tissue damage and to promote wound healing and tissue remodeling. Moderate systemic levels of the hormone might confer a survival advantage with respect to bacterial or viral infection by providing a useful mobilization of energy reserves for the acute metabolic demands of inflammatory responses. In sharp contrast to these beneficial effects, prolonged exposure to even low levels of cachectin/TNF might contribute to the cachexia associated with many chronic disease states. Rapid uncontrolled production of cachectin/TNF, like that observed in response to endotoxemia or overwhelming gram-negative sepsis, could act systemically to induce the metabolic derangements of septic shock leading to cardiovascular collapse, acute organ failure, and death.