MECHANISMS OF ACTION OF THE TUMOR-NECROSIS-FACTOR AND LYMPHOTOXIN LIGAND-RECEPTOR SYSTEM

In the past few years, a number of experimental observations have prov ided more insight into the mechanisms of action of tumor necrosis fact or (TNF)/lymphotoxin (LT) ligand-receptor system. This system consists of three ligands, TNF, LT alpha (LT alpha) and LT beta (LT beta), and three membrane-associated receptors, p55, p75 and LT beta-receptor (L T beta-R). Like TNF, LT alpha is a secreted protein which in solution forms a homotrimer molecule, with a conformation similar to that of TN F, LT beta is a transmembrane protein that provides the membrane ancho r for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta. This complex retains a structure related to TNF and LT alpha homotrimers, with the homology regions interacting in a heterotypic fashion. The LT alpha(1):LT beta(2) heteromer has been fou nd to be a predominant form of surface LT. The biological effects of T NF and LT alpha homotrimers are mediated by p55 and p75 receptors, whi le the heteromeric complex of LT alpha/LT beta transduces its cellular signal via LT beta-R. Membrane-associated receptor affinities as well as final biological effects of TNF/LT can be modulated by the influen ce of naturally occuring soluble receptors, derived from the cell surf ace by proteolytic cleavage. The multimerization of receptor cytoplasm ic domains upon TNF/LT ligation is postulated to activate the intracel lular signal-transduction pathways, One of them is the activation of p hospholipase A(2) (PL-A(2)) resulting in the production of arachidonic acid (AA) and other metabolites, including leukotriens, prostaglandin s, and 5-hydroperoxyeicosatetraenoic acid (5HPETE). The second pathway involves phosphatidylcholine-specific phospholipase C (PC-PLC) with s ubsequent production of diacylglycerol (DAG) and activation of protein kinase C (PKC). As a third signaling pathway, TNF/LT employ the sphin gomyelinase (SMase)-mediated hydrolysis of membrane sphingomyelin (SM) to ceramide. The final link in the TNF/LT signaling is activation of nuclear transcription factors, such as NF-kappa B, AP-1, interferon re gulatory factors-1 and -2 (IRF-1, IRF-2), and NF-GMa. Since induction of AP-1, IRF-1 and IRF-2 as well as NF-GMa proceeds through translatio nal event, the posttranslational TNF/LT-driven activation of NF-KB rem ains the only cellular event identified so far that serves as a direct target in their signaling cascade.