First printed in R&D Systems' 1996 Catalog.
Interleukin 15 (IL-15) is a novel cytokine that shares many biological properties with, but lacks amino acid sequence homology to, IL-2. IL-15 was originally identified in media conditioned by a monkey kidney eipthelial cell line (CVI/EBNA) based on its mitogenic activity on the murine T cell line, CTLL-2.1 IL-15 was also independently discovered as a cytokine produced by a human adult T cell leukemia cell line (HuT-102) that stimulated T cell proliferation and was designated IL-T.2
|Figure 1. A structural comparison between the IL-15R alpha and the IL-2R alpha (adapted from Giri, J.G. et al. (1995) EMBO J. 14:3654). Disulfide bridges characteristic of the sushi domain are shown.
Human, simian and mouse IL-15 cDNA, as well as human and mouse IL-15 genomic clones, have been isolated and characterized.1,3,4 The IL-15 cDNA clones from all three species encode a 162 amino acid (aa) residue precursor protein containing a 48 aa residue leader that is cleaved to generate the 114 aa residue mature IL-15. Human IL-15 shares approximately 97% and 73% sequence identity with simian and mouse IL-15, respectively. Both human and simian IL-15 are active on mouse cells. Although the structure of IL-15 has not been determined, it is predicted to be similar to IL-2 and other members of the four-helix bundle cytokine family.3,5
High-affinity cell surface receptors for IL-15 have been detected on a variety of T cells and B cells, as well as non-lymphoid cells.7,8 It has been demonstrated that the beta and the gamma common chain subunits of the IL-2 high-affinity receptor complex are also required for IL-15 signal transduction and efficient internalization.8 Recently, a novel mouse IL-15-specific binding protein (IL-15R alpha) that is structurally related to the alpha subunit of the IL-2 high-affinity receptor has been cloned and characterized.8 IL-15R alpha shares structural similarities with the IL-2R alpha and both proteins contain the short consensus "sushi domain" repeats. Whereas both human and simian IL-15 can bind to a complex of the human beta and gamma common chain subunits in the absence of the mouse IL-15R alpha subunit, simian IL-15 is not capable of binding to and transducing IL-15 signals through the mouse beta and gamma common chain complex alone. Soluble human IL-2R beta appears to bind human IL-15 with sufficiently high affinity such that it is an excellent IL-15 antagonist.9
IL-15 mRNAs have been detected in a number of human tissues and cell types, including heart, lung, liver, placenta, skeletal muscle, adherent peripheral blood mononuclear cells, and epithelial and fibroblast cell lines. However, IL-15 mRNA is not detectable in activated peripheral blood T cells that contain high levels of IL-2 mRNA.1 The IL-15 mRNA from normal cells has been shown to contain 10 upstream AUGs that attenuate IL-15 mRNA translation.4 Thus, in spite of the high levels of IL-15 mRNA present in adherent peripheral blood mononuclear cells, IL-15 protein is not detectable in the culture supernatant using a sensitive ELISA.6
IL-15 has biological activities similar to IL-2 and has been shown to stimulate the growth of natural killer cells, activated peripheral blood T lymphocytes1,7,8, tumor infiltrating lymphocytes (TILs)10, and B cells.11 In addition, IL-15 has also been shown to be a chemoattractant for human blood T lymphocytes12 and to be able to induce lymphokine-activated killer (LAK) activity in NK cells as well as to be able to induce the generation of cytolytic effector cells. It is likely that additional, as yet unidentified, functions for IL-15 will be discovered in the future.
By virtue of its activity as a stimulator of T cells, NK cells, LAK cells, and TILs, IL-2 is currently in clinical trials testing its potential use in treatments for cancer and for viral infections. Because of its similar biological activities, IL-15 should have similar therapeutic potential.
- Grabstein, K. et al. (1994) Science 264:965.
- Burton, J.C. et al. (1994) Proc. Natl. Acad. Aci. USA 91:4935.
- Anderson, D.M. et al. (1995) Genomics 25:701.
- Bamford, R.N. et al. (1995) Cytokine 7:595.
- Brandhuber, B.J. et al. (1987) Science 238:1707.
- R&D Systems, unpublished results.
- Giri, J.G. et al. (1994) EMBO J. 13:2822.
- Giri, J.G. et al. (1995) EMBO J. 15:3654.
- R&D Systems, unpublished results.
- Lewko,W. M. et al. (1995) Cancer Biother. 10:13.
- Armitage, R.J. et al. (1995) J. Immunol. 154:483.
- P. Wilkinson and F. Liew (1995) J. Exp. Med. 181:1255.