Interleukin-21 signaling: functions in cancer and autoimmunity.
Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4(+) T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21-specific alpha chain (IL-21Ralpha; JAK/STAT) that heterodimerizes with the common gamma chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.
Ludwig-Austin Joint Medical Oncology Unit, Austin Health, Melbourne, Australia. Ian.Davis@ludwig.edu.au
Ian D
ID
Davis
Kresten
K
Skak
Mark J
MJ
Smyth
Paul E G
PE
Kristjansen
Dennis M
DM
Miller
Pallavur V
PV
Sivakumar
D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000098546:Interleukin-21
D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21