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Interleukin 15

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Interleukin 15 (IL-15) is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor 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.

Expression

Interleukin - 15 (IL-15) was discovered in 1994 by two different laboratories, and characterized as T cell growth factor.[1] Together with interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 7 (IL-7), interleukin 9 (IL-9), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) belonging to the four α-helix bundle family of cytokine.[1][2]

IL-15 is constitutively expressed by a large number of cell types and tissues, including monocytes, macrophages, dendritic cells (DC), keratinocytes, fibroblasts and nerve cells.[3] As a pleiotropic cytokine plays an important role in innate and adaptive immunity.[4]

Gene

IL -15 is 14-15 kDa glycoprotein encoded by the 34 kb region 4q31 of chromosome 4, and by the central region of chromosome 8 in mice.[5] The human IL-15 gene comprises nine exons (1 - 8 and 4A) and eight introns, four of which (exons 5 through 8) code for the mature protein (Figure 1).[1]

Figure 1. IL -15 is 14-15 kDa glycoprotein encoded by the 34 kb region on chromosome 4q31, and by central region of chromosome 8 in mice. The human IL-15 gene comprises nine exons (1 - 8 and 4A) and eight introns, four of which (exons 5 through 8) code for the mature protein.

Two alternatively spliced transcript variants of this gene encoding the same protein have been reported.[6] The originally identified isoform, with long signal peptide of 48 amino acids (IL-15 LSP) consisted of a 316 bp 5’-untranslated region (UTR), 486 bp coding sequence and the C-terminus 400 bp 3’-UTR region. The other isoform (IL-15 SSP) has a short signal peptide of 21 amino acids encoded by exons 4A and 5.[1] Both isoforms shared 11 amino acids between signal sequences of the N-terminus.[7] Although both isoforms produce the same mature protein, they differ in their cellular trafficking.[1] IL-15 LSP isoform was identified in Golgi apparatus [GC], early endosomes and in the endoplasmic reticulum (ER). It exists in two forms, secreted and membrane-bound particularly on dendritic cells. On the other hand IL-15 SSP isoform is not secreted and it appears to be restricted to the cytoplasm and nucleus where plays an important role in the regulation of cell cycle.[1]

It has demonstrated that two isoforms of IL-15 mRNA are generated by alternatively splicing in mice. Isoform which had and alternative exon 5 containing another 3’ splicing site, exhibited a high translational efficiency, and the product lack hydrophobic domains in the signal sequence of the N-terminus. This suggesting that the protein derived from this isoform is located intracellulary. The other isoform with normal exon 5, which is generated by integral splicing of the alternative exon 5, may be released extracellulary.[8]

Although IL-15 mRNA can be found in many cells and tissues including mast cells, cancer cells or fibroblasts, this cytokine is produce as a mature protein mainly by dendritic cells, monocytes and macrophages. This discrepancy between the wide appearance of IL-15 mRNA and limited production of protein might be explained by the presence of the twelve in humans and five in mice upstream initiating codons, which can repress translation of IL-15 mRNA. Translational inactive mRNA is stored within the cell and can be induce upon specific signal.[9] Expression of IL-15 can be stimulated by cytokine such as GM-CSF, double-strand mRNA, unmethylated CpG oligonucleotides, lipopolysaccharide (LPS) through Toll-like receptors (TLR), interferon gamma (IFN-γ) or after infection of monocytes herpes virus, Mycobacterium tuberculosis and Candida albicans (Figure 2).[10]

Figure 2. The originally identified isoform, with long signal peptide of 48 amino acids (IL-15 LSP) consisted of a 316 bp 5’-untraslated region (UTR), 486 bp coding sequence and on the C-terminus 400 bp 3’-UTR region. The other isoform (IL-15 SSP) has a short signal peptide of 21 amino acids encoded by exons 4A and 5. Both isoforms shared 11 amino acids between signal sequences of the leader peptides.



Signaling

Figure 3. The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα. Signaling pathway of IL-15 begins with biding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface.
Figure 4. IL-15 bind to IL-15Rα receptor alone with affinity (Ka = 1.1011/M). It can also bind to IL-15Rβγc signaling complex with lower affinity (Ka = 1.109/M).
Figure 5. Signaling pathway of IL-15 begins with biding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface. Upon binding IL-15β subunit activates Janus kinase 1 (Jak1) and γc subunit Janus kinase 2 (Jak2), which leads to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) and STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these cytokines have similar downstream effects including the induction of B-cell lymphoma (Bcl-2), MAP (mitogen-activated protein kinase) kinase pathway and the phosphorylation of Lck (lymphocyte-activated protein tyrosine kinase) and Syk (spleen tyrosine kinase) kinases, which leads to cell proliferation and maturation.
Figure 6. The second mechanism pof IL-15 action is cis-presentation, when il-15 is presented by IL-15Rα to 15Rβγc signaling complex on the same cell. This mechanism is mediated by the C-terminus flexibility which is mediated by 32 amino acids linker and/or 74 amino acids long PT region.

The prevailing mechanism of IL-15 action seems to be juxtacrine signaling or also determined as cell-to-cell contact. It also includes intracrine and reverse signaling. IL-15 was initially characterized as a soluble molecule. Later it was shown that IL-15 also exists as a membrane-bound form which represents the major form of IL-15 protein. In membrane-bound form it could be bound directly to cellular membrane or presented by IL-15Rα receptor.[9]

The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα (Figure 3).[11] IL-15 bind to IL-15Rα receptor alone with affinity (Ka = 1.1011/M). It can also bind to IL-15Rβγc signaling complex with lower affinity (Ka = 1.109/M) (Figure 4).[4]

Signaling pathway of IL-15 begins with binding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface. Upon binding IL-15β subunit activates Janus kinase 1 (Jak1) and γc subunit Janus kinase 2 (Jak2), which leads to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) and STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these cytokines have similar downstream effects including the induction of B-cell lymphoma (Bcl-2), MAP (mitogen-activated protein kinase) kinase pathway and the phosphorylation of Lck (lymphocyte-activated protein tyrosine kinase) and Syk (spleen tyrosine kinase) kinases, which leads to cell proliferation and maturation (Figure 5).[4][12]

In mast cells, the IL-15R signaling pathway has been found to include Jak2 and STAT5 instead Jak1/3 and STAT3/5. Phosphorylation STATs form transcription factors and activate transcription of appropriate genes. The β chain of IL-15R recruits and also activates protein tyrosine kinases of the Src family including Lck, Fyn and Lyn kinase. It also activates phosphatidylinositol 3-kinase (PI3K) and AKT signaling pathway and induce expression of transcription factors including c-Fos, c-Jun, c-Myc and NF-κB.[9]

IL-15 is also able to bind to the 15Rβγc signaling complex with intermediate affinity without requirement for IL-15Rα rreceptor. Upon binding IL-15 to signaling complex activates kinases of the Src family including Lck and Fyn, which subsequently activates PI3K and MAPK signaling pathway.[13] The second mechanism pof IL-15 action is cis-presentation, when il-15 is presented by IL-15Rα to 15Rβγc signaling complex on the same cell. This mechanism is mediated by the C-terminus flexibility which is mediated by 32 amino acids linker and/or 74 amino acids long PT region (Figure 6).[11]

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).[6] In humans with celiac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducing Bcl-2 and/or Bcl-xL.[14]

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.[15]

Celiac disease

There have been recent studies suggesting that suppression of IL-15 may be a potential treatment for celiac disease and even presents the possibility of preventing its development. In one study with mice blocking IL-15 with an antibody led to the reversal of autoimmune intestinal damage.[16] In another study mice used were able to eat gluten without developing symptoms.[17]

Immunotherapy

Metastatic cancer

IL-15 has been shown to enhance the anti-tumor immunity of CD8+ T cells in pre-clinical models.[18][19] 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.[20]

References

  1. ^ a b c d e f Steel JC, Waldmann TA, Morris JC (2012). "Interleukin-15 biology and its therapeutic implications in cancer". Trends Pharmacol. Sci. 33 (1): 35–41. doi:10.1016/j.tips.2011.09.004. PMID 22032984. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Di Sabatino A, Calarota SA, Vidali F, Macdonald TT, Corazza GR (2011). "Role of IL-15 in immune-mediated and infectious diseases". Cytokine Growth Factor Rev. 22 (1): 19–33. doi:10.1016/j.cytogfr.2010.09.003. PMID 21074481. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ a b c Lodolce JP, Burkett PR, Koka RM, Boone DL, Ma A (2002). "Regulation of lymphoid homeostasis by interleukin-15". Cytokine Growth Factor Rev. 13 (6): 429–39. PMID 12401478. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Waldmann TA, Tagaya Y (1999). "The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens". Annu. Rev. Immunol. 17: 19–49. doi:10.1146/annurev.immunol.17.1.19. PMID 10358752.
  6. ^ a b "Entrez Gene: IL15 interleukin 15".
  7. ^ Tagaya Y, Kurys G, Thies TA, Losi JM, Azimi N, Hanover JA, Bamford RN, Waldmann TA (1997). "Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides". Proc. Natl. Acad. Sci. U.S.A. 94 (26): 14444–9. PMC 25016. PMID 9405632. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Nishimura H, Yajima T, Naiki Y, Tsunobuchi H, Umemura M, Itano K, Matsuguchi T, Suzuki M, Ohashi PS, Yoshikai Y (2000). "Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo". J. Exp. Med. 191 (1): 157–70. doi:10.1084/jem.191.1.157. PMC 2195806. PMID 10620614. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b c Jakobisiak M, Golab J, Lasek W (2011). "Interleukin 15 as a promising candidate for tumor immunotherapy". Cytokine Growth Factor Rev. 22 (2): 99–108. doi:10.1016/j.cytogfr.2011.04.001. PMID 21531164. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Bamford RN, DeFilippis AP, Azimi N, Kurys G, Waldmann TA (1998). "The 5' untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control". J. Immunol. 160 (9): 4418–26. PMID 9574546. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b Olsen SK, Ota N, Kishishita S, Kukimoto-Niino M, Murayama K, Uchiyama H, Toyama M, Terada T, Shirouzu M, Kanagawa O, Yokoyama S (2007). "Crystal Structure of the interleukin-15.interleukin-15 receptor alpha complex: insights into trans and cis presentation". J. Biol. Chem. 282 (51): 37191–204. doi:10.1074/jbc.M706150200. PMID 17947230. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  12. ^ Schluns KS, Stoklasek T, Lefrançois L (2005). "The roles of interleukin-15 receptor alpha: trans-presentation, receptor component, or both?". Int. J. Biochem. Cell Biol. 37 (8): 1567–71. doi:10.1016/j.biocel.2005.02.017. PMID 15896666. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Perera PY, Lichy JH, Waldmann TA, Perera LP (2012). "The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use". Microbes Infect. 14 (3): 247–61. doi:10.1016/j.micinf.2011.10.006. PMID 22064066. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Sauce D, Larsen M, Curnow SJ, Leese AM, Moss PA, Hislop AD, Salmon M, Rickinson AB (2006). "EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15". Blood. 108 (1): 11–8. doi:10.1182/blood-2006-01-0144. PMID 16543467. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B (2011). "Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens". Nature. 471 (7337): 220–4. doi:10.1038/nature09849. PMC 3076739. PMID 21307853. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Yokoyama S, Watanabe N, Sato N, Perera PY, Filkoski L, Tanaka T, Miyasaka M, Waldmann TA, Hiroi T, Perera LP (2009). "Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes". Proc. Natl. Acad. Sci. U.S.A. 106 (37): 15849–54. doi:10.1073/pnas.0908834106. PMC 2736142. PMID 19805228. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlén C, Greenberg PD (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ "A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer". ClinicalTrials.gov.

Further reading

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