Molecular pathways: interleukin-15 signaling in health and in cancer

Abstract

Interleukin-15 (IL-15) is a proinflammatory 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.

Figure 1. Intracellular signaling of IL-15

In one scenario (right), IL-15 binds to its high affinity IL-15Rα expressed on an antigen-presenting cell and in turn is presented in trans to the IL-2/15Rβγ heterodimer. From there, effector cell activation can proceed via three distinct pathways: one involves JAK-STAT activation with the phosphorylated STAT proteins forming a heterodimer and trafficking to the nucleus for transcriptional activation; a second pathway involves the recruitment of Shc to a phosphorylated site on the IL-2/15Rβ chain followed by activation of Grb2. From there, Grb2 can proceed down a PI3K pathway to phosphorylate Akt, or can bind the guanine nucleotide exchange factor SOS to activate RAS-RAF and ultimately MAPK. Each contributes to effector cell survival and activation. In mast cells (left), IL-15 signals through a unique receptor chain, IL-15RX, to activate the JAK2/STAT5 pathway. IL-15 can also bind to the common γ chain to transmit its signals via Tyk2/STAT6 for initiation of a survival (Bcl-X_L) and a Th2 immune response. Therapeutic interventions using anti-IL-15R antibody prevents binding and signaling of IL-15 through its receptor. Pharmacological inhibitors targeting the JAK/STAT pathway prevent activation and translocation of the STAT heterodimer to the nucleus. Finally, proteasomal inhibitors such as bortezomib prevent activation of NF-κB and Myc. Each of these therapies targets IL-15 signaling in malignant cells, but may have consequences for normal cells dependent upon IL-15.