TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis (original) (raw)

Abstract

The members of the tumor necrosis factor (TNF) family play pivotal roles in the regulation of the immune system. Here we describe a new ligand in this family, designated TWEAK. The mouse and human versions of this protein are unusually conserved with 93% amino acid identity in the receptor binding domain. The protein was efficiently secreted from cells indicating that, like TNF, TWEAK may have the long range effects of a secreted cytokine. TWEAK transcripts were abundant and found in many tissues, suggesting that TWEAK and TRAIL belong to a new group of widely expressed ligands. Like many members of the TNF family, TWEAK was able to induce interleukin-8 synthesis in a number of cell lines. The human adenocarcinoma cell line, HT29, underwent apoptosis in the presence of both TWEAK and interferon-␥. Thus, TWEAK resembles many other TNF ligands in the capacity to induce cell death; however, the fact that TWEAK-sensitive cells are relatively rare suggests that TWEAK along with lymphotoxins ␣/␤ and possibly CD30L trigger death via a weaker, nondeath domain-dependent mechanism. Cytokines of the TNF 1 family are mediators of host defense and immune regulation. Members of this family act either locally through direct cell-to-cell contact or as secreted proteins capable of diffusing to more distant targets. These proteins are synthesized as type II membrane proteins with the extracellular C-terminal region mediating binding to the receptors of the TNF receptor (TNF-R) family (1). The TNF family of ligands and receptors comprises at least 14 unique signaling pathways including TNF, lymphotoxins (LT), Fas, CD27, CD30, CD40, 4 -1BB, OX-40, TRAMP (also DR3, WSL-1, Apo-3), CAR-1, TRAIL, GITR, HVEM, osteoprotegerin, and NGF (2-12). Excluding NGF, each of these signaling pathways is likely to be * This work was supported in part by Grants 31-42275.94 and 32-41729.94 (to I. G.) from the Swiss National Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank TM /EBI Data Bank with accession number(s) AF030099 and AF030100.

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