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Interleukin 15

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IL15
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesIL15,IL-15, interleukin 15
External IDsOMIM:600554;MGI:103014;HomoloGene:487;GeneCards:IL15;OMA:IL15 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3600

16168

Ensembl

ENSG00000164136

ENSMUSG00000031712

UniProt

P40933

P48346

RefSeq (mRNA)

NM_000585
NM_172174
NM_172175

NM_001254747
NM_008357

RefSeq (protein)

NP_000576
NP_751915

NP_001241676
NP_032383

Location (UCSC)Chr 4: 141.64 – 141.73 MbChr 8: 83.06 – 83.13 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Interleukin-15(IL-15) is aproteinthat in humans is encoded by the IL15gene.IL-15 is an inflammatorycytokinewith structural similarity to Interleukin-2 (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 thecommon gamma chain(gamma-C, CD132). IL-15 is secreted bymononuclear phagocytes(and some other cells) following infection byvirus(es). This cytokine induces theproliferationofnatural killer cells,i.e. cells of theinnate immune systemwhose principal role is to kill virally infected cells.

Expression

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IL-15 was discovered in 1994 by two different laboratories, and characterized asT cellgrowth factor.[5]Together withInterleukin-2(IL-2),Interleukin-4(IL-4),Interleukin-7(IL-7),Interleukin-9(IL-9),granulocyte colony-stimulating factor(G-CSF), andgranulocyte-macrophage colony-stimulating factor(GM-CSF), IL-15 belongs to the four α-helix bundle family ofcytokines.[5][6]

IL-15 is constitutively expressed by a large number ofcell typesandtissues,includingmonocytes,macrophages,dendritic cells(DC),keratinocytes,fibroblasts,myocyteandnerve cells.[7]As a pleiotropic cytokine, it plays an important role ininnateandadaptive immunity.[8]

Gene

[edit]
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.
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.

IL-15 is 14–15 kDaglycoproteinencoded by the 34 kb region ofchromosome4q31 in humans, and at the central region ofchromosome 8inmice.[9]The human IL-15genecomprises nineexons(1–8 and 4A) and eightintrons,four of which (exons 5 through 8) code for the matureprotein(Figure 1).[5]

Two alternatively spliced transcript variants of thisgeneencoding the sameproteinhave been reported.[10]The originally identifiedisoform,with longsignal peptideof 48amino acids(IL-15 LSP) consisted of a 316 bp5'-untranslated region(UTR), 486 bpcoding sequenceand the C-terminus 400 bp3'-UTRregion. The other isoform (IL-15 SSP) has a short signal peptide of 21 amino acids encoded byexons4A and 5.[5]Both isoforms shared 11 amino acids betweensignal sequencesof the N-terminus.[11]Although both isoforms produce the same mature protein, they differ in theircellular trafficking.[5]IL-15 LSP isoform was identified inGolgi apparatus[GC], earlyendosomesand in theendoplasmic reticulum(ER). It exists in two forms, secreted and membrane-bound particularly ondendritic cells.On the other hand, IL-15 SSP isoform is not secreted and it appears to be restricted to thecytoplasmandnucleuswhere plays an important role in the regulation ofcell cycle.[5]

It has been demonstrated that two isoforms of IL-15 mRNA are generated by alternativesplicingin mice. The isoform which had an alternative exon 5 containing another 3' splicing site, exhibited a hightranslationalefficiency, and the product lackhydrophobicdomainsin thesignal sequenceof 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.[12]

Although IL-15mRNAcan be found in manycellsandtissuesincludingmast cells,cancer cellsorfibroblasts,thiscytokineis produced as a mature protein mainly bydendritic cells,monocytesandmacrophages.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 represstranslationof IL-15 mRNA. Translational inactive mRNA is stored within the cell and can be induced upon specific signal.[13]Expression of IL-15 can be stimulated by cytokine such asGM-CSF,double-strand mRNA,unmethylated CpG oligonucleotides,lipopolysaccharide(LPS) throughToll-like receptors(TLR),interferon gamma(IFN-γ) or after infection of monocytesherpes virus,Mycobacterium tuberculosisandCandida albicans(Figure 2).[14]

Signaling

[edit]
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 binding 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 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 3 (Jak3), 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 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.

The prevailing mechanism of IL-15 action seems to bejuxtacrine signalingor 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-15protein.In membrane-bound form it could be bound directly tocellular membraneor presented byIL-15Rα receptor.[13]

The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα (Figure 3).[15]IL-15 bind to IL-15Rα receptor alone with anaffinityofKa= 1.1011/M. It can also bind to IL-15Rβγcsignaling complex with lower affinity (Ka= 1.109/M) (Figure 4).[8]

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 activatesJanus kinase 1(Jak1) and γc subunitJanus kinase 3(Jak3), which leads tophosphorylationand activation ofsignal transducer and activator of transcription 3(STAT3) andSTAT5.[16]Due to sharing ofreceptorsubunits betweenIL-2and IL-15, both of thesecytokineshave similar downstream effects including the induction ofBcl-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).[8][17]

Inmast cells,the IL-15Rsignaling pathwayhas 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.[13]

IL-15 is also able to bind to the 15Rβγcsignaling complex with intermediate affinity without requirement for IL-15Rα receptor. Upon binding IL-15 to signaling complex, kinases of the Src family including Lck and Fyn are activated, and subsequently activates PI3K andMAPK signaling pathway.[18]The second mechanism of IL-15 action is cis-presentation, when IL-15 is presented by IL-15Rα to 15Rβγcsignaling 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).[15]

Function

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IL-15 regulates the activation and proliferation ofTandnatural killer(NK) cells. 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 preventsapoptosisby inducingBCL2L1/BCL-x(L), an inhibitor of the apoptosis pathway.[10]In humans withceliac diseaseIL-15 similarly suppresses apoptosis in T-lymphocytes by inducingBcl-2and/orBcl-xL.[19]

Ahematopoietinreceptor, theIL-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 calledInterleukin 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,andSTAT6transcription factorsare activated to elicit downstream signaling events.

IL-15 and its receptor subunit Alpha (IL-15Rα) are also produced by skeletal muscle in response to different exercise doses (myokine), playing significant roles in visceral (intra-abdominal or interstitial) fat reduction[20][21]and myofibrillar protein synthesis (hypertrophy).[22]

Evolution

[edit]

All classes of jawed vertebrates, including sharks, share anIL-15gene at a conserved genomic location.[23]Unusual features of IL-15 that appear to be conserved throughout jawed vertebrate evolution are (1) multiple AUGs in the transcript 5’ untranslated region,[14][24](2) an unusually long N-terminal hydrophobic (leader) sequence,[14][23]and (3) a dependency on the formation of what might be considered “heterodimer cytokine” complexes with IL-15Rα for stability.[25]The latter probably helps to retain IL-15 activity at the surface of the expressing cell and therefore within restricted tissue niches, while the reasons for (1) and (2) are still not known. In fish, the gene duplication resulting in mammalian IL-2Rα and IL-15Rα[26]has not occurred yet,[27][28]and the molecules IL-2, IL-15, andIL-15-like(IL-15L) all share the same receptor Alpha chain[25][29]which looks like mammalian IL-15Rα.[27][30]In fish, as in mammals, IL-15 appears to stimulate type 1 (Th1) immunity.[24][25][31]

In jawless fish or invertebrates, homologues of IL-15 have not been found.

Disease

[edit]

Epstein–Barr virus

[edit]

In humans with history of acuteinfectious mononucleosis(the syndrome associated with primaryEpstein–Barr virusinfection), IL-15R expressing lymphocytes are not detected even 14 years after infection.[32]

Celiac disease

[edit]

There have been recent studies suggesting that suppression of IL-15 may be a potential treatment forceliac diseaseand 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.[33]In another study mice used were able to eatglutenwithout developing symptoms.[34]

Non-alcoholic fatty liver disease

[edit]

A recent report indicated IL-15 promotesnon-alcoholic fatty liver disease.[35]

Rheumatoid arthritis

[edit]

A recent study found IL-15 present in the synovial tissue of patients diagnosed with rheumatoid arthritis. Preliminary research has functionally implicated IL-15 role in collagen-induced arthritis.[36]

Immunotherapy

[edit]

Metastatic cancer

[edit]

IL-15 has been shown to enhance the anti-tumor immunity of CD8+ T cells in pre-clinical models.[37][38]Aphase I clinical trialto evaluate the safety, dosing, and anti-tumorefficacyof IL-15 in patients withmetastaticmelanomaandrenal cell carcinoma(kidney cancer) has begun toenrollpatients at theNational Institutes of Health.[39]

Vaccines Adjuvants

[edit]

Vector-based therapy – Nonlytic Newcastle Disease Virus (NDV) was engineered to express recombinant IL-15 protein to generate an NDV-modified tumor vaccine. Preclinical results of NDV-modified tumor vaccine showed promise by controlling melanoma tumor growth in mice.[40]A recombinant vaccinia virus expressing influenza A proteins and IL-15 promoted cross protection by CD4+ T cells.[41]A Brucella DNA vaccine containing IL-15 gene enhanced the CD8+ T cell immune response in mice.[42]IL-15 was needed for CD4+ T cell heterosubtypic protection while using a multivalent influenza vaccine using vaccinia-based vector.[41]While influenza A virus expressing IL-15 stimulates both innate and adaptive immune cells to decrease tumor growth mice.[43]

Transpresentation complexes

[edit]

Currently there are two varieties of IL-15 superagonist available. One combines IL-15 and IL-15Rα-Fc (R&D Systems)in vitroto generate the complex. It is referred to as IL-15 SA. A second IL-15 superagonist complex called ALT-803 is offered by Altor BioScience.

IL-15 SA

[edit]

IL-15 SA is currently being evaluated for antiviral and anticancer activities, in addition to enhancing immunotherapy and vaccination.[44][45]One potential shortcoming of IL-15 SA was its enhancement of septic shock in mice.[46]

Nogapendekin alfa inbakicept

[edit]

Nogapendekin alfa inbakicept (ALT-803) is an IL-15 superagonist complex IL-15N72D:IL-15RαSu/Fc that includes an IL-15 mutant (IL-15N72D) and a dimeric IL-15 receptor α sushi domain-IgG1 Fc fusion protein.[47][48]

ALT-803 was givenfast trackstatus by the FDA in 2017 and at that time, Phase III trials in bladder cancer were being prepared.

Nanrilkefusp alfa

[edit]

Nanrilkefusp alfa (RLI-15) is a fusion protein consisting of the NH2-terminal (amino acids 1–77, sushi+) cytokine-binding domain ofIL-15Rαcoupled to IL-15 via a 20-amino acid flexible linker. This fusion protein, referred to as protein receptor-linker-IL-15 (RLI-15) acts as an IL-15 superagonists specifically binding with high affinity the mid-affinity IL-2/IL-15 receptor formed byIL2RBand theCommon gamma chain(γcorCD132), that has an increased serum half-life and biological activity similar to complexed IL-15/IL-15Rα-Fc. RLI-15 demonstrated a strong anti-tumor effect in two different tumor models.[49]RLI-15 is being produced and tested by Cytune Pharma affiliated company ofSOTIOwhich renamed it to SO-C101, later to SOT101.[50]Phase 1 trial was initiated in 2019.[51]

Rheumatoid arthritis

[edit]

Possible implications of IL-15 treatment for individuals diagnosed with rheumatoid arthritis (RA). HuMax-IL15 was derived from transgenic mice and individuals with RA underwent HuMax-IL15 administration for twelve weeks. After treating synovial tissue with HuMax-IL15, decreased proliferation of interferon-y and suppressed expression of CD69 was observed. Additionally, 63% of patients reported a 20% improvement while 25% of patients reported a 70% improvement. American College of Rheumatology criteria were used to determine the severity of RA symptoms.[36]

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[edit]
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Further reading

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