Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family.

Abstract

Apoptosis has been implicated as a physiologic cell death program critical for homeostasis. Dysregulation of apoptosis may be involved in human diseases such as cancer, AIDS, degenerative and autoimmune diseases, and infectious diseases. Apoptosis may also play important roles in lung diseases in two different ways. First, failure to clear unwanted cells by apoptosis will prolong the inflammation because of the release of their toxic contents. Repair after an acute lung injury requires the elimination of proliferating mesenchymal and inflammatory cells from the alveolar air space or alveolar wall (1). Second, excessive apoptosis may cause disease. An intratracheal injection of agonistic anti-Fas antibody into adult mice causes epithelial cell apoptosis and lung inflammation, which subsequently leads to pulmonary fibrosis (2). DNA damage and apoptosis in lung epithelial cells have been reported in acute lung injury (3), diffuse alveolar damage (4), and idiopathic pulmonary fibrosis (IPF) (5). Therefore, epithelial cell injury is the common manifestation of lung injury, and apoptosis contributes to such injury of epithelial cells. Tumor necrosis factor (TNF)a is a proinflammatory cytokine, which can induce a broad spectrum of biologic effects and is associated with inflammatory lung disease. TNF causes inflammation by damaging tissues and by inducing the expression of adhesion molecules and cytokines in epithelial and endothelial cells, as well as in inflammatory cells. The cellular effects of TNF are mediated by two distinct cell surface receptors termed TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (6). Most cytotoxic effects of TNF are mediated by TNFR1 through interaction of its death domain with the TNFR-associated death domain protein (TRADD) (7). TRADD interacts with Fas-associated death domain protein (FADD) (8) to activate caspase-8, thereby initiating the apoptosis pathway. Death domain is the sequence in TNFR1, TRADD, and FADD. The death domain is a protein–protein interaction domain, and adopter molecules FADD and TRADD use these domains to interact with other death domain– containing molecules and trigger the apoptosis-signaling pathway. Another well known death receptor, Fas, also transduces apoptosis signal through FADD and shares the same signaling machinery downstream of FADD with TNFR (Figure 1). Since the Fas-mediated apoptosis-signaling pathway is relatively short and straight compared with that of TNFR, Fas-ligation takes hours to kill target cells, whereas TNF takes a day or more. Furthermore, TNF does not usually kill most type of cells without metabolic inhibitors, which is different from Fas-ligation. Although TNFR mediates apoptotic signal transduction, it can transduce intracellular signals that activate transcription factor nuclear factor k B (NFk B) by proteolytic breakdown of the inhibitor of k B (I k B). TNFR-associated factor-2 (TRAF2) and receptor interacting protein (RIP) (9) indirectly bind to TNFR1 through TRADD or directly bind to TNFR2 and activate the NFk B–inducing kinase (NIK) (10), which in turn activates the inhibitor of I k B kinase (IKK) complex (11–14). IKK phosphorylates I k B, which leads to I k B degradation and allows NFk B to translocate to the nucleus and activate transcription (Figure 1). TNF or agonistic anti-Fas antibody administration can lead to production of interleukin-8 (IL-8) by colon epithelial cells (15) or by bronchial epithelial cells, in addition to inducing apoptosis in vitro (16). As TNF activates the IL-8 promoter transcriptionally via NFk B activation, IL-8 secretion induced by Fas ligation also seems to be regulated via NFk B activation (16). It has been reported that the kinase activity of NIK is part of the signaling cascade that leads to NFk B activation and that this signaling pathway is common to TNFR and Fas (10). Disruption of the NFk B pathway with the dominant-negative TRAF2 enhances the cytolytic effects of TNF (17). NFk B subunit RelAdeficient (RelA 2 / 2 ) mouse fibroblasts and macrophages with TNF result in a significant reduction in viability, whereas RelA 1 / 1 cells were unaffected (18). Therefore, death receptor activation induces NFk B activation, which triggers inflammation and also plays an important role in regulating apoptosis. Cellular proteins homologous to baculovirus inhibitors of apoptosis (IAPs) block cell death. TRAF1, TRAF2, XIAP, c-IAP1, and c-IAP2 were identified as gene targets of NFk B transcriptional activity (19). The caspases are a family of cystein proteases, and it is now thought that many forms of cell death are ultimately dependent on caspase activation (Figure 1). XIAP, c-IAP1, and c-IAP2 are direct ( Received in original form November 24, 1999 )