Elsevier

Gene

Volume 204, Issues 1–2, 19 December 1997, Pages 35-46
Gene

Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells1

https://doi.org/10.1016/S0378-1119(97)00509-XGet rights and content

Abstract

A novel (TL1), a recently described (TL2) TNF-like, and three recently described TNF receptor-like (TR1, TR2, TR3) molecules were identified by searching a cDNA database. TL1 and TL2 are type-II membrane proteins. TR2 and TR3 are type-I membrane proteins whereas TR1 appears to be a secreted protein. TL1, TL2, TR2 and TR3 were expressed in hematopoietic cells, whereas TR1 was not. Northern blots hybridized with the cDNA probes revealed multiple forms of RNA as well as inducible expression of TL1, TL2, TR2 and TR3. TL2 and TR3, in particular, were highly induced in activated CD4+ T cells. Radiation hybrid mapping localized TR1 and TL2 to 8q24 and 3q26, respectively, which are not near any known superfamily members. TL1 was mapped to 9q32, near CD30L (9q33) and TR2 and TR3 mapped to the region of chromosome 1 that contains the TNFR-II, 4-1BB, OX40 and CD30 gene cluster at 1p36. Only TR3 in this cluster possesses a death domain. Southern blot analysis revealed the presence of TL and TR genes in different mammalian species. TL2, TR1, TR2 and TR3 were recently described by others as TRAIL/Apo-2L, OPG, HVEM and DR3/WSL-1/Apo-3/TRAMP/LARD, respectively.

Introduction

The rapidly expanding TNF superfamily of cytokines comprises TNF-α, LTα (also called TNF-β), LTβ, CD27L, CD30L, CD40L (gp39), FasL, 4-1BBL and OX40L (Armitage, 1994; Beutler and van Huffel, 1994a, Beutler and van Huffel, 1994b; Cosman, 1994; Gruss and Dower, 1995). These cytokines are type-II membrane proteins except for LTα, which is a secreted protein. TNF-α, FasL and CD40L also exist as soluble proteins that are proteolytically cleaved from the membrane surface (Banchereau et al., 1994; Cosman, 1994; Graf et al., 1995). Members of this superfamily show a relatively low level of sequence conservation, with an intermolecule sequence homology within the C-terminal extracellular domain ranging from 15 to 34%. The receptors (type-I transmembrane glycoproteins exhibiting sequence and structure homology) for these cytokines are: the three known TNF receptors, TNFR-I (p60), TNFR-II (p80) and TNFR-III (TNFR-RP), CD27, CD30, CD40, Fas (CD95/Apo1), 4-1BB, and OX40 (see references above). The other member of this superfamily is the p75 low affinity nerve growth factor receptor LNGFR (Gruss and Dower, 1995; Johnson et al., 1986). The cytoplasmic domains of TNFR-I, LNGFR and Fas are characterized by the presence of the so-called `death domain', a unique sequence motif which appears to be essential for mediating signals leading to cell death. Similar motifs have also been described for the Drosophila apoptotic protein REAPER and for a series of recently identified molecules such as FADD, TRADD and RIP (Cleveland and Ihle, 1995; Muzio et al., 1996). Functionally, the ligands and their respective receptors have been implicated in activation, proliferation, differentiation, aggregation, apoptosis, factor secretion, tissue remodeling, and organogenesis in diverse cells and tissues. Although their involvement in the regulation of the hematopoietic system is by far the best understood, members of this superfamily have also been implicated in the regulation of other non-hematopoietic systems (Aggarwal and Natarajan, 1996).

In addition, several transcriptionally active virus-encoded open reading frames which belong to the TNFR superfamily have been identified, including SFV-T2 in Shope fibroma virus, MYX-T2 in Myxoma virus, Va53 or SaIF19R in Vaccinia virus, G4R in Variola virus and crmB in Cowpox. These ORFs encode soluble forms of the TNFR-superfamily proteins capable of binding to and blocking TNF-α action (Banchereau et al., 1994; Smith et al., 1994). Another member of this rapidly expanding superfamily includes the fungal pathogenic protein ECP1 (Van den Ackerveken et al., 1993), which has been implicated in the subversion of anti-fungal host defense mechanisms of tomato plants.

Our study describes a novel and a recently described member of the TNF superfamily and three recently described members of the TNFR superfamily.

Section snippets

cDNAs

The following cDNA clones were obtained from HGS: HUVE091 (=TL1), HTPAN08 (=TL2), HSABH13 (=TR1), HTXBS40 (=TR2) and HTTBN61 (=TR3).

Cells

Unless stated otherwise, cell lines were obtained from the American Type Culture Collection (Rockville, MD). The myeloid (Koeffler, 1983; Tucker et al., 1987) and B-cell lines (Jonak et al., 1992) studied represent cell types at different stages of the differentiation pathways. KG1a and PLB 985 cells were obtained from H.P. Koeffler (UCLA School of Medicine). BJAB

Identification of genes belonging to the TNF ligand and TNF receptor superfamilies

We have identified several genes that belong to the TNF Ligand and Receptor superfamilies by searching the HGS human cDNA database. The nomenclature used in this paper is TL (1, 2, etc.) for the TNF Ligand-related molecules and TR (1, 2, etc.) for the TNF Receptor-related molecules. TL1, TL2, TR1, TR2 and TR3 were identified by their identities (percent shown in parentheses) to human TNF-α (30%), mouse FasL (27%), TNFR-II (28%), mouse CD40 (29%) and TNFR-I (37%), respectively.

While our

Discussion

We describe here a comparative study of two TL and three TR genes together with TNF-α and OX40. These genes were expressed in the human brain, heart, lung, thymus, spleen, kidney, small intestine and prostate, thus indicating that they may play important roles in the pathophysiology of these tissues. Even if they are not expressed in particular tissues, the TL and TR genes may still be involved in the functions of these tissues if their respective receptors or ligands are expressed in these

Acknowledgements

We thank Zdenka Jonak and Phil Koeffler for cell lines; Paul Lysko for providing monocyte RNA, Jeff Stadel for endothelial cell RNA; Stephanie Van Horn, Wendy Fuetterer and Joyce Mao for sequencing; Sally Lyn, Yen Sen Ho and Mark Hurle for sequence analysis, and Josephine Fox for manuscript preparation. The TL, TR and OX40 cDNA clones and TL1 probe were obtained from HGS.

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1

This work was presented in a poster at the Keystone Symposium on Tolerance and Autoimmunity, Keystone, Colorado, 13–19 April 1997.

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