Interleukin 15

Source: Wikipedia, the free encyclopedia.
IL15
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Interleukin-15 (IL-15) is a

mononuclear phagocytes (and some other cells) following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system
whose principal role is to kill virally infected cells.

Expression

IL-15 was discovered in 1994 by two different laboratories, and characterized as

GM-CSF), IL-15 belongs to the four α-helix bundle family of cytokines.[5][6]

IL-15 is constitutively expressed by a large number of

adaptive immunity.[8]

Gene

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 kDa

introns, four of which (exons 5 through 8) code for the mature protein (Figure 1).[5]

Two alternatively spliced transcript variants of this

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.[5]

It has been demonstrated that two isoforms of IL-15 mRNA are generated by alternative 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.[12]

Although IL-15

IFN-γ) or after infection of monocytes herpes virus, Mycobacterium tuberculosis and Candida albicans (Figure 2).[14]

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 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 be

IL-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).

affinity of Ka = 1.1011/M. It can also bind to IL-15Rβγc signaling 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 activates

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]

In

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.[13]

IL-15 is also able to bind to the 15Rβγc signaling 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 and

MAPK signaling pathway.[18] 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).[15]

Function

IL-15 regulates the activation and proliferation of

BCL2L1/BCL-x(L), an inhibitor of the apoptosis pathway.[10] In humans with celiac disease IL-15 similarly suppresses apoptosis in T-lymphocytes by inducing Bcl-2 and/or Bcl-xL.[19]

A

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.

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

All classes of jawed vertebrates, including sharks, share an IL-15 gene at a conserved genomic location.

IL-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

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.[32]

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.[33] In another study mice used were able to eat gluten without developing symptoms.[34]

Non-alcoholic fatty liver disease

A recent report indicated IL-15 promotes

non-alcoholic fatty liver disease.[35]

Rheumatoid arthritis

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

Metastatic cancer

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

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.[39]

Vaccines Adjuvants

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

Currently there are two varieties of IL-15 superagonist available. One combines IL-15 and IL-15Rα-Fc (R&D Systems) in vitro to 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

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

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 given fast track status by the FDA in 2017 and at that time, Phase III trials in bladder cancer were being prepared.

Nanrilkefusp alfa

Nanrilkefusp alfa (RLI-15) is a fusion protein consisting of the NH2-terminal (amino acids 1–77, sushi+) cytokine-binding domain of

CD132), 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 of SOTIO which renamed it to SO-C101, later to SOT101.[50] Phase 1 trial was initiated in 2019.[51]

Rheumatoid arthritis

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]

References

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Further reading
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