The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens.
Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15R beta and gamma c subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15R alpha. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in activated T cells. In addition to its other functional activities in immune and nonimmune cells, IL-15 plays a pivotal role in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.
Waldmann
T A
TA
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. tawald@helix.nih.gov
Tagaya
Y
Y
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics* / Q000502:physiology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000502:physiology; D012192:Retroviridae Infections / Q000276:immunology; D015398:Signal Transduction
D018076:DNA, Complementary; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2