Molecular Pathways: Interleukin-15 Signaling in Health and in Cancer

Abstract

Interleukin-15 (IL-15) is a pro-inflammatory cytokine involved in the development, survival, proliferation and activation of multiple lymphocyte lineages utilizing a variety of signaling pathways. IL-15 utilizes three distinct receptor chains in at least two different combinations to signal and exert its effects on the immune system. The binding of IL-15 to its receptor complex activates an ‘immune-enhancing’ signaling cascade in natural killer cells and subsets of T cells, as well as the induction of a number of proto-oncogenes. Additional studies have explored the role of IL-15 in the development and progression of cancer, notably leukemia of large granular lymphocytes, cutaneous T-cell lymphoma and multiple myeloma. This review provides an overview of the molecular events in the IL-15 signaling pathway and the aberrancies in its regulation that are associated with chronic inflammation and cancer. We briefly explore the potential therapeutic opportunities that have arisen as a result of these studies to further the treatment of cancer. These involve both targeting the disruption of IL-15 signaling as well as IL-15-mediated enhancement of innate and antigen specific immunity.

Short Term Hypoxia Synergizes with Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities

“…During an active immune response, the ability of NK cells to respond to activation is substantially enhanced through IL-15, which is produced by monocytes, macrophages, and dendritic cells. IL-15 initiates Janus kinasesignal transducer and activator of transcription (Jak-Stat) signaling that promotes growth of cytotoxic lymphocytes, including NK cells (15,16). Recently, NK cell treatment with IL-15, in addition to stimulation by cytokines (IL-2, -12, and -18) and binding of ligands for activating NK receptors, was shown to support switching to glycolytic metabolism, which involves nutrient-sensing mechanistic target of rapamycin (mTor) signaling and is a requirement for production of Ifn-␥ and cytolytic effector molecules (17)(18)(19)(20).…”

IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis

“…JAK1 and JAK3) and STATs (i.e. STAT3 and STAT5) signaling molecules, the two cytokines share several functions (Pelletier et al 2002, Mishra et al 2014, including the stimulation of the proliferation of activated CD4 − CD8 − , CD4 + CD8 + , CD4 + , and CD8 + T cells , Waldmann 2006, Steel et al 2012, Johnston et al 1995. They also stimulate the generation, proliferation, and activation of NK cells .…”

CD56bright NK cells exhibit potent antitumor responses following IL-15 priming

“…IL-15/IL-15Rα can associate with IL-15Rβ/γ either on the same cell (cis-presentation) or on a different cell (trans-presentation) to initiate signaling, although trans-presentation is thought to be the major IL-15R trigger in vivo (22,23). Three primary pathways are activated downstream of the IL-15R: JAK1/3/STAT3/5, PI3K/Akt/ mTOR, and Ras/Raf/MEK/ERK (23,24). Through these pathways, IL-15 has been shown to promote the survival and proliferation of CD56 bright and CD56 dim NK cells, and to enhance the cytotoxicity of the CD56 dim subset (25).…”