Interleukin 15
Interleukin 15 (IL-15) is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain (CD122) and the common gamma chain (gamma-C, CD132). IL-15 is secreted by mononuclear phagocytes (and some other cells) following infection by virus(es). This cytokine induces cell proliferation of natural killer cells; cells of the innate immune system whose principal role is to kill virally infected cells.
Gene
Two alternatively spliced transcript variants of this gene encoding the same protein have been reported.[1] In humans, interleukin 15 is encoded by the IL15 gene.[2]
Function
Interleukin 15 (IL-15) regulates T and natural killer (NK) cell activation and proliferation. Survival signals that maintain memory T cells in the absence of antigen are provided by IL-15. This cytokine is also implicated in NK cell development. In rodent lymphocytes, IL-15 prevents apoptosis by inducing an apoptosis inhibitor, BCL2L1/BCL-x(L).[1] In humans with celiac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducing Bcl-2 and/or Bcl-xL.[3]
A hematopoietin receptor, the IL-15 receptor, that binds IL-15 propagates its function. Some subunits of the IL-15 receptor are shared in common with the receptor for a structurally related cytokine called interleukin 2 (IL-2) allowing both cytokines to compete for and negatively regulate each other's activity. CD8+ memory T cell number is controlled by a balance between IL-15 and IL-2. When IL-15 binds its receptor, JAK kinase, STAT3, STAT5, and STAT6 transcription factors are activated to elicit downstream signaling events.
Disease
Epstein-Barr Virus
In humans with history of acute infectious mononucleosis (the syndrome associated with primary Epstein-Barr virus infection), IL-15R expressing lymphocytes are not detected--even 14 years after infection.
Immunotherapy
Metastatic Cancer
IL-15 has been shown to enhance the anti-tumor immunity of CD8+ T cells in pre-clinical models.[4][5] A phase I clinical trial to evaluate the safety, dosing, and anti-tumor efficacy of IL-15 in patients with metastatic melanoma and renal cell carcinoma (kidney cancer) has begun to enroll patients at the National Institutes of Health.[6]
References
- ^ a b "Entrez Gene: IL15 interleukin 15". http://www.ncbi.nlm.nih.gov/gene/3600.
- ^ Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M (May 1994). "Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor". Science 264 (5161): 965–8. doi:10.1126/science.8178155. PMID 8178155.
- ^ Malamut G, El Machhour R, Montcuquet N, Martin-Lannerée S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B (June 2010). "IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis". J. Clin. Invest. 120 (6): 2131–43. doi:10.1172/JCI41344. PMC 2877946. PMID 20440074. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2877946.
- ^ Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, Grewal N, Spiess PJ, Antony PA, Palmer DC, Tagaya Y, Rosenberg SA, Waldmann TA, Restifo NP (February 2004). "IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells". Proc. Natl. Acad. Sci. U.S.A. 101 (7): 1969–74. doi:10.1073/pnas.0307298101. PMC 357036. PMID 14762166. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=357036.
- ^ Teague RM, Sather BD, Sacks JA, et al. (March 2006). "Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors". Nat. Med. 12 (3): 335–41. doi:10.1038/nm1359. PMID 16474399.
- ^ "A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer". ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT01021059.
Further reading
- Maślińska D (2001). "The cytokine network and interleukin-15 (IL-15) in brain development". Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 39 (2): 43–7. PMID 11680634.
- Liew FY, McInnes IB (2002). "Role of interleukin 15 and interleukin 18 in inflammatory response". Ann. Rheum. Dis. 61 Suppl 2 (Suppl 2): ii100–2. doi:10.1136/ard.61.suppl_2.ii100. PMC 1766710. PMID 12379638. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1766710.
- Lodolce JP, Burkett PR, Koka RM, et al. (2003). "Regulation of lymphoid homeostasis by interleukin-15". Cytokine Growth Factor Rev. 13 (6): 429–39. doi:10.1016/S1359-6101(02)00029-1. PMID 12401478.
- Mattei Fabrizio, Schiavoni G., Belardelli F., Tough D.F. (2001). "IL-15 is expressed by dendritic cells in response to Type I IFN, Double-stranded RNA, or Lipopolysaccharide and promotes dendritic cell activation". J. Immunol. 167 (3): 1179–87. PMID 11466332.
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IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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