TNFSF18 (tumor necrosis factor (ligand) superfamily, member 18)

	Figure 1. Schematic illustration of the gene structure of human TNFSF18 on chromosome 1. Both published transcript variants are shown. Red boxes represent the mRNA transcript within the gene. The smaller boxes at the beginning and the end of the transcripts indicate untranslated regions, while the larger boxes display the translated parts.
Description	2 transcript versions published: mRNA 748 bp: 3 exons (1-223, 224-254, 255-748) -> coding for 199 aa (2-601), mRNA 610 bp: 3 exons (1-176, 177-207, 208-610) -> coding for 177 aa (21-554).
Transcription	Accurate start codon is not clearly defined, 2 transcript versions are published (differing start codons in exon 1).
Pseudogene	Unknown.

	Figure 2. Schematic illustration of the structure of TNFSF18 protein versions, according to the two published transcripts.
Description	TNFSF18/GITR ligand (GITRL) is a single-pass type II transmembrane protein and contains 2 potential glycosylation sites (predicted at 129 aa and 161 aa). TNFSF18 encompasses 177 or 199 aa and thus has a molecular weight of about 20 kDa. In the 177 aa long version, amino acids 1-28 constitute the cytoplasmic domain, 29-49 the transmembrane domain, and 50-177 the extracellular domain, whereas in the 199 aa long variant the amino acids 1-50 constitute the cytoplasmic domain, 51-71 the transmembrane domain, and 72-199 the extracellular domain.
Expression	TNFSF18 is expressed on DC, monocytes, macrophages, B cells, activated T cells, endothelial cells, osteoclasts and various healthy non-lymphoid tissues (e.g., testis, ...). The fact that TNFSF18 is constitutively expressed on resting antigen-presenting cells distinguishes it from most other TNF family members, which are not detectable in resting state and are upregulated following activation. In addition, TNFSF18 is constitutively expressed and released as soluble form by solid tumors of different histological origin and various hematopoietic malignancies.
Localisation	TNFSF18 is a type II transmembrane protein. A soluble form of the molecule has been shown to be released by a yet unknown mechanism e.g. by tumor cells.
Function	TNFSF18 is the only known ligand for GITR (TNFRSF18, AITR), which is mainly expressed by lymphatic cells like T lymphocytes and NK cells. Upon interaction with its receptor, TNFSF18 is, like many other TNF family members, capable to transduce bidirectional signals, i.e. in the receptor and the ligand bearing cell. Transduction of signals into TNFSF18 bearing cells has been shown to cause differentiation of osteoclasts, to activate macrophages and to alter cytokine production of healthy myeloid cells, but also of carcinoma and leukemia cells and influences apoptosis. Activation of macrophages via TNFSF18 results in increased secretion of inflammatory mediators like MMP-9, NO and TNF. In healthy macrophages and myeloid leukemia cells, TNFSF18 signaling has been found to involve the MAP kinase pathway. Binding to TNFRSF18 may induce signaling through this receptor, which, in mice, has been implicated in the development of autoimmune diseases, graft versus host disease and in the immune response against infectious pathogens and tumors. Available data suggest that TNFRSF18 may mediate different effects in mice and men, and most functional studies regarding the role of TNFRSF18 in tumor immunology have been performed using agonistic antibodies or injection of adenovirus expressing recombinant TNFSF18 into tumors, which might not reflect the consequences of TNFRSF18 interaction with its natural ligand in vivo. In line, studies evaluating immune responses in GITR-/- mice have so far not led to a clear picture of the role of TNFRSF18 in normal physiology.
Homology	The TNFSF18 gene is conserved in human, chimpanzee, dog, mouse, and rat. The homology among the other TNF family members is highest with OX40L.

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