Identification of a New Member of the Tumor Necrosis Factor Family and Its Receptor, a Human Ortholog of Mouse GITR

Curr Biol. 1999 Feb 25;9(4):215-8. doi: 10.1016/s0960-9822(99)80093-1.

Abstract

The tumor necrosis factor (TNF) and TNF receptor (TNFR) gene superfamilies regulate diverse biological functions, including cell proliferation, differentiation, and survival [1] [2] [3]. We have identified a new TNF-related ligand, designated human GITR ligand (hGITRL), and its human receptor (hGITR), an ortholog of the recently discovered murine glucocorticoid-induced TNFR-related (mGITR) protein [4]. The hGITRL gene mapped to chromosome 1q23, near the gene for the TNF homolog Fas/CD95 ligand [5]. The hGITR gene mapped to chromosome 1p36, near a cluster of five genes encoding TNFR homologs [1] [6]. We found hGITRL mRNA in several peripheral tissues, and detected hGITRL protein on cultured vascular endothelial cells. The levels of hGITR mRNA in tissues were generally low; in peripheral blood T cells, however, antigen-receptor stimulation led to a substantial induction of hGITR transcripts. Cotransfection of hGITRL and hGITR in embryonic kidney 293 cells activated the anti-apoptotic transcription factor NF-kappaB, via a pathway that appeared to involve TNFR-associated factor 2 (TRAF2) [7] and NF-kappaB-inducing kinase (NIK) [8]. Cotransfection of hGITRL and hGITR in Jurkat T leukemia cells inhibited antigen-receptor-induced cell death. Thus, hGITRL and hGITR may modulate T lymphocyte survival in peripheral tissues.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cells, Cultured
  • Chromosome Mapping
  • Chromosomes, Human, Pair 1*
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation
  • Glucocorticoid-Induced TNFR-Related Protein
  • Humans
  • Mice
  • Molecular Sequence Data
  • Multigene Family
  • Proteins / metabolism
  • RNA, Messenger / analysis
  • Receptors, Nerve Growth Factor / chemistry
  • Receptors, Nerve Growth Factor / genetics*
  • Receptors, Nerve Growth Factor / physiology
  • Receptors, Tumor Necrosis Factor / chemistry
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / physiology
  • Recombinant Proteins / biosynthesis
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • TNF Receptor-Associated Factor 2
  • Transcription, Genetic*
  • Transfection
  • Tumor Necrosis Factor-alpha / chemistry
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • Glucocorticoid-Induced TNFR-Related Protein
  • Proteins
  • RNA, Messenger
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 2
  • TNFRSF18 protein, human
  • Tnfrsf18 protein, mouse
  • Tumor Necrosis Factor-alpha