Interleukin 15

Interleukin 15 (IL-15) is a is_associated_with::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 is_associated_with::virus(es). This cytokine induces is_associated_with::cell proliferation of is_associated_with::natural killer cells; cells of the is_associated_with::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 is_associated_with::T cell is_associated_with::growth factor. Together with is_associated_with::interleukin 2 (IL-2), is_associated_with::interleukin 4 (IL-4), is_associated_with::interleukin 7 (IL-7), is_associated_with::interleukin 9 (IL-9), is_associated_with::granulocyte colony-stimulating factor (is_associated_with::G-CSF), and is_associated_with::granulocyte-macrophage colony-stimulating factor (is_associated_with::GM-CSF), IL-15 belongs to the four α-helix bundle family of is_associated_with::cytokine.

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

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

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

It has been demonstrated that two isoforms of IL-15 mRNA are generated by alternatively splicing in mice. The isoform which had an 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 suggests 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.

Although IL-15 is_associated_with::mRNA can be found in many cells and tissues including is_associated_with::mast cells, is_associated_with::cancer cells or is_associated_with::fibroblasts, this is_associated_with::cytokine is produce as a mature protein mainly by is_associated_with::dendritic cells, is_associated_with::monocytes and is_associated_with::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 induced upon specific signal. Expression of IL-15 can be stimulated by cytokine such as is_associated_with::GM-CSF, double-strand mRNA, unmethylated CpG oligonucleotides, is_associated_with::lipopolysaccharide (LPS) through is_associated_with::Toll-like receptors (TLR), is_associated_with::interferon gamma (is_associated_with::IFN-γ) or after infection of monocytes herpes virus, is_associated_with::Mycobacterium tuberculosis and is_associated_with::Candida albicans (Figure 2).

Signaling


The prevailing mechanism of IL-15 action seems to be is_associated_with::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 is_associated_with::protein. In membrane-bound form it could be bound directly to is_associated_with::cellular membrane or presented by IL-15Rα receptor.

The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα (Figure 3). 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).

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 is_associated_with::Janus kinase 1 (Jak1) and γc subunit is_associated_with::Janus kinase 2 (Jak2), which leads to is_associated_with::phosphorylation and activation of signal transducer and activator of transcription 3 (is_associated_with::STAT3) and is_associated_with::STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these is_associated_with::cytokines have similar downstream effects including the induction of B-cell lymphoma (Bcl-2), MAP (is_associated_with::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).

In is_associated_with::mast cells, the IL-15R is_associated_with::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.

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. The second mechanism of 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).

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 is_associated_with::apoptosis by inducing an apoptosis inhibitor, BCL2L1/BCL-x(L). In humans with celiac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducing is_associated_with::Bcl-2 and/or is_associated_with::Bcl-xL.

A hematopoietin receptor, the is_associated_with::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 is_associated_with::interleukin 2 (IL-2) allowing both cytokines to compete for and negatively regulate each other's activity. is_associated_with::CD8+ memory T cell number is controlled by a balance between IL-15 and IL-2. When IL-15 binds its receptor, JAK kinase, is_associated_with::STAT3, is_associated_with::STAT5, and is_associated_with::STAT6 is_associated_with::transcription factors are activated to elicit downstream signaling events.

As a is_associated_with::myokine, interleukin-15 appears to play a significant role in the reduction of visceral (intra-abdominal or interstitial) fat.

Epstein-Barr virus
In humans with history of acute is_associated_with::infectious mononucleosis (the syndrome associated with primary is_associated_with::Epstein-Barr virus infection), IL-15R expressing lymphocytes are not detected—even 14 years after infection.

Celiac disease
There have been recent studies suggesting that suppression of IL-15 may be a potential treatment for is_associated_with::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. In another study mice used were able to eat is_associated_with::gluten without developing symptoms.

Metastatic cancer
IL-15 has been shown to enhance the anti-tumor immunity of CD8+ T cells in pre-clinical models. A is_associated_with::phase I clinical trial to evaluate the safety, dosing, and anti-tumor is_associated_with::efficacy of IL-15 in patients with metastatic is_associated_with::melanoma and is_associated_with::renal cell carcinoma (kidney cancer) has begun to enroll patients at the is_associated_with::National Institutes of Health.