Interleukin 24

Last updated
IL24
IL24 protein.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL24 , C49A, FISP, IL10B, MDA7, MOB5, ST16, IL-24, interleukin 24
External IDs OMIM: 604136; MGI: 2135548; HomoloGene: 4991; GeneCards: IL24; OMA:IL24 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

11009

93672

Ensembl

ENSG00000162892

ENSMUSG00000026420

UniProt

Q13007

Q925S4

RefSeq (mRNA)

NM_001185156
NM_001185157
NM_001185158
NM_006850
NM_181339

Contents

NM_053095

RefSeq (protein)

NP_001172085
NP_001172086
NP_001172087
NP_006841

NP_444325

Location (UCSC) Chr 1: 206.9 – 206.9 Mb Chr 1: 130.81 – 130.82 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin 24 (IL-24) is a protein in the interleukin family, a type of cytokine signaling molecule in the immune system. In humans, this protein is encoded by the IL24 gene.

IL-24 is a cytokine belonging to the IL-10 family of cytokines that signals through two heterodimeric receptors: IL-20R1/IL-20R2 and IL-22R1/IL-20R2. This interleukin is also known as melanoma differentiation-associated 7 (mda-7) due to its discovery as a tumour suppressing protein. IL-24 appears to control cell survival and proliferation by inducing rapid activation of particular transcription factors called STAT1 and STAT3. This cytokine is predominantly released by activated monocytes, macrophages and T helper 2 (Th2) cells [5] and acts on skin, lung, and reproductive tissues. IL-24 performs important roles in wound healing, arthritis, psoriasis and cancer. [6] [7] [8] Several studies have shown that cell death occurs in cancer cells/cell lines following exposure to IL-24. [9] [10] The gene for IL-24 is located on chromosome 1 in humans. [11]

Structure

The structure of IL-24 has been found through crystallization by fusing a flexible linker with a ligand to its two receptors, IL-22R1 and IL-20R2. The structure revealed that there is a lack of disulfides, which is present in most cytokines, and is likely the reason why IL-24 is unstable compared to other interleukins. [12]

IL-24 is a secreted protein that is highly conserved throughout evolution with sequence homology between species including yeast, dog, cat, monkey and cow. It is located on chromosome 1q32-33 in humans along with several other IL-10 cytokine family gene members. IL-24 encompasses seven exons and six introns. The cDNA of IL-24 is 1,718 base pairs in length and encodes a protein of 206 amino acid with a predicted molecular size of ˜24 kDa. IL-24 also contains an IL-10 signature motif at amino acids 101–121 shared by other IL-10 family member cytokines. IL-24 possibly can form functionally active dimers due to the presence of potential disulfide bonds. Researchers identified a number of splice variants of IL-24 lacking one or more exons. [13] The signal peptide in IL-24 is two times the length as in other related human cytokines (51 amino acids), and the predicted molecular mass of IL-24 monomer is 18.3 kDa. [14]

Function

IL-24 functions as a cytokine (at low concentrations). Its normal physiological role is connected with wound healing (In normal skin cells, it suppress keratinocyte proliferation during wound healing [15] ), and protection against diseases caused by bacteria (for example Mycobacterim tuberculosis , Salmonella typhimurium , Pseudomonas aeruginosa ). It is also important in autoimmune diseases such as psoriasis, rheumatoid arthritis or spondyloarthropathy.

IL-24's Role in the Jak/STAT Pathway

IL-24 carries its functions through two types of membrane receptors (IL-22R1/IL-20R2 and IL-20R1/IL-20R2) with simultaneous activation of the JAK/signal transducer and activator of transcription (STAT) pathway within their cytoplasmic domains. [16] IL-24 is a type of cytokine that interacts frequently with class 2 cytokine receptors. IL-24 can form IL-20R1/IL-20R2 and IL-22R1/IL-20R2 which are shared with the other IL-20SFCs and IL-22. IL-20SFC is an IL-20 subfamily of cytokines which includes IL-19, IL-20, and IL-24. They all signal through the common chain that is IL-20R2. Through these two types of membrane receptors (IL-22R1/IL-20R2 and IL-20R1/IL-20R2), simultaneous activation of the JAK/signal transducer and activator of transcription (STAT) pathway within their cytoplasmic domains. [16]

Although it belongs to the same group of cytokines as IL-10, it has different effect on the immune system. IL-10 is a suppressive cytokine that suppresses inflammation while also maintaining immunomodulatory functions. Beside the normal physiological roles, IL-24 inhibits tumor growth, invasion, metastasis and angiogenesis. [17]

Production of IL-24 by Different Cells

IL-24 can be produced by myeloid cells (in response to microbial products through TLRs), lymphoid cells, and epithelial cells in response to cytokine stimulation. IL-24 can also dampen the first rounds of CD8 cell expansion to prevent uncontrolled T cell responses. After the combination of anti-IgM and CD40-L stimulation, B lymphocytes can also induce IL-24 expression. In response to immune cells, non-lymphoid cells such as melanocytes can also produce IL-24. [18]

Cancer

IL-24 is an immunomodulatory cytokine which can also display broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and induction of cancer-specific apoptosis. Given its ubiquitous apoptotic effect on malignant cells, lack of an effect on normal cells, and absence of significant side effects, IL-24 is an important candidate for cancer therapy. [19]

IL-24 is able to induce apoptosis via both intracellular and extracellular signaling mechanisms. Secreted IL-24 protein induces a robust expression of endogenous IL-24 and subsequent induction of tumor-specific killing through an ER stress-mediated pathway as well as by ROS production. The ER stress is the initial pathway in IL-24-induced apoptosis. [19]

An important question, which remained unresolved, is why IL-24 has the abilities to selectively induce apoptosis in a large spectrum of human cancer-derived cell lines without harming normal cells. One possible reason for this differential killing effect involves inherent biochemical differences between normal and cancer cells (ER stress, ROS production and ceramide), another possibility is that IL-24 is able to target a molecule that only triggers apoptosis in cancer cells. The third option for this differential killing effect is that both of the above hypotheses are correct. [19]

IL-24 is able to induce toxic autophagy in cancer cells in vitro and animal models in vivo. Past independent studies have also proven that the cytokine can play a role in inflammation for inflammatory bowel disease, psoriasis, cardiovascular disease, rheumatoid arthritis, tuberculosis, and viral infection. [20]

Secondary cytokines that evoke antitumor immune responses are stimulated by IL-24. These secondary cytokines include TNF-α, IFN-gamma, and IL-1, which induce apoptosis. [21] IL-24 also inhibits cancer by blocking VEGF and TGF-alpha activities through inhibition of Src, a proto-oncogene, within tumor cells and inhibiting epithelial cell differentiation. [22] IL-24 also induces apoptosis By inducing more stress on the endoplasmic reticulum. [23]

Related Research Articles

<span class="mw-page-title-main">Tumor necrosis factor</span> Protein

Tumor necrosis factor (TNF), formerly known as TNF-α, is an inflammatory protein and a principal mediator of the innate immune response. TNF is produced primarily by macrophages in response to antigens, and activates inflammatory pathways through its two receptors, TNFR1 and TNFR2. It is a member of the tumor necrosis factor superfamily, a family of type II transmembrane proteins that function as cytokines. Excess production of TNF plays a critical role in the pathology of several inflammatory diseases, and anti-TNF therapies are often employed to treat these diseases.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with 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 the common gamma chain. IL-15 is secreted by mononuclear phagocytes 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.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 20</span> Protein-coding gene in the species Homo sapiens

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

<span class="mw-page-title-main">MAP3K7</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.

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Leukotriene B<sub>4</sub> receptor 2 Protein-coding gene in humans

Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice.

<span class="mw-page-title-main">IL17RA</span> Protein-coding gene in the species Homo sapiens

Interleukin 17 receptor A, also known as IL17RA and CDw217, is a human gene.

<span class="mw-page-title-main">Interleukin-21 receptor</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Interleukin 20 receptor, alpha subunit</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Interleukin 20 receptor, beta subunit</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

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Anticancer genes have a special ability to target and kill cancer cells without harming healthy ones. They do this through processes like programmed cell death, known as apoptosis, and other mechanisms like necrosis and autophagy. In the late 1990s, researchers discovered these genes while studying cancer cells. Sometimes, mutations or changes in these genes can occur, which might lead to cancer. These changes can include small alterations in the DNA sequence or larger rearrangements that affect the gene's function. When these anticancer genes are lost or altered, it can disrupt their ability to control cell growth, potentially leading to the development of cancer.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162892 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026420 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Poindexter NJ, Walch ET, Chada S, Grimm EA (September 2005). "Cytokine induction of interleukin-24 in human peripheral blood mononuclear cells". Journal of Leukocyte Biology. 78 (3): 745–52. doi:10.1189/jlb.0205116. PMID   16000394. S2CID   1329942.
  6. ↑ Wang M, Liang P (February 2005). "Interleukin-24 and its receptors". Immunology. 114 (2): 166–70. doi:10.1111/j.1365-2567.2005.02094.x. PMC   1782067 . PMID   15667561.
  7. ↑ Kragstrup TW, Otkjaer K, Holm C, Jørgensen A, Hokland M, Iversen L, Deleuran B (January 2008). "The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy" (PDF). Cytokine. 41 (1): 16–23. doi:10.1016/j.cyto.2007.10.004. PMID   18061474.
  8. ↑ Kragstrup TW, Greisen SR, Nielsen MA, Rhodes C, Stengaard-Pedersen K, Hetland ML, et al. (March 2016). "The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression". Arthritis Research & Therapy. 18 (1): 61. doi: 10.1186/s13075-016-0964-7 (inactive 2024-09-17). PMC   4788924 . PMID   26968800.{{cite journal}}: CS1 maint: DOI inactive as of September 2024 (link)
  9. ↑ Fisher PB, Gopalkrishnan RV, Chada S, Ramesh R, Grimm EA, Rosenfeld MR, et al. (2003). "mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic". Cancer Biology & Therapy. 2 (4 Suppl 1): S23-37. doi: 10.4161/cbt.458 . PMID   14508078.
  10. ↑ Sauane M, Lebedeva IV, Su ZZ, Choo HT, Randolph A, Valerie K, et al. (May 2004). "Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways". Cancer Research. 64 (9): 2988–93. doi:10.1158/0008-5472.CAN-04-0200. PMID   15126330.
  11. ↑ IL24 GeneCard
  12. ↑ Lubkowski J, Sonmez C, Smirnov SV, Anishkin A, Kotenko SV, Wlodawer A (October 2018). "Crystal Structure of the Labile Complex of IL-24 with the Extracellular Domains of IL-22R1 and IL-20R2". Journal of Immunology. 201 (7): 2082–2093. doi:10.4049/jimmunol.1800726. PMC   6143405 . PMID   30111632.
  13. ↑ Emdad L, Bhoopathi P, Talukdar S, Pradhan AK, Sarkar D, Wang XY, et al. (July 2019). "Recent insights into apoptosis and toxic autophagy: The roles of MDA-7/IL-24, a multidimensional anti-cancer therapeutic". Seminars in Cancer Biology. 66: 140–154. doi:10.1016/j.semcancer.2019.07.013. PMC   7009777 . PMID   31356866.
  14. ↑ Fuson KL, Zheng M, Craxton M, Pataer A, Ramesh R, Chada S, Sutton RB (October 2009). "Structural mapping of post-translational modifications in human interleukin-24: role of N-linked glycosylation and disulfide bonds in secretion and activity". The Journal of Biological Chemistry. 284 (44): 30526–33. doi: 10.1074/jbc.M109.036061 . PMC   2781607 . PMID   19734147.
  15. ↑ Whitaker EL, Filippov VA, Duerksen-Hughes PJ (December 2012). "Interleukin 24: mechanisms and therapeutic potential of an anti-cancer gene". Cytokine & Growth Factor Reviews. 23 (6): 323–31. doi:10.1016/j.cytogfr.2012.08.004. PMID   22981288.
  16. 1 2 Wang M, Tan Z, Zhang R, Kotenko SV, Liang P (March 2002). "Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2". The Journal of Biological Chemistry. 277 (9): 7341–7. doi: 10.1074/jbc.M106043200 . PMID   11706020.
  17. ↑ Menezes ME, Bhatia S, Bhoopathi P, Das SK, Emdad L, Dasgupta S, et al. (2014). "MDA-7/IL-24: Multifunctional Cancer Killing Cytokine". Anticancer Genes. Advances in Experimental Medicine and Biology. Vol. 818. pp. 127–53. doi:10.1007/978-1-4471-6458-6_6. ISBN   978-1-4471-6457-9. PMC   4633013 . PMID   25001534.
  18. ↑ Persaud L, De Jesus D, Brannigan O, Richiez-Paredes M, Huaman J, Alvarado G, et al. (June 2016). "Mechanism of Action and Applications of Interleukin 24 in Immunotherapy". International Journal of Molecular Sciences. 17 (6): 869. doi: 10.3390/ijms17060869 . PMC   4926403 . PMID   27271601.
  19. 1 2 3 Persaud L, De Jesus D, Brannigan O, Richiez-Paredes M, Huaman J, Alvarado G, et al. (June 2016). "Mechanism of Action and Applications of Interleukin 24 in Immunotherapy". International Journal of Molecular Sciences. 17 (6): 869. doi: 10.3390/ijms17060869 . PMC   4926403 . PMID   27271601. CC-BY icon.svg Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  20. ↑ Menezes ME, Bhoopathi P, Pradhan AK, Emdad L, Das SK, Guo C, et al. (2018). "Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases". Advances in Cancer Research. 138. Elsevier: 143–182. doi:10.1016/bs.acr.2018.02.005. ISBN   978-0-12-815127-3. PMC   6218935 . PMID   29551126.
  21. ↑ Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, et al. (June 2002). "The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24". Journal of Immunology. 168 (12): 6041–6. doi: 10.4049/jimmunol.168.12.6041 . PMID   12055212.
  22. ↑ Mhashilkar AM, Stewart AL, Sieger K, Yang HY, Khimani AH, Ito I, et al. (August 2003). "MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells". Molecular Therapy. 8 (2): 207–19. doi: 10.1016/s1525-0016(03)00170-9 . PMID   12907143.
  23. ↑ Sauane M, Su ZZ, Gupta P, Lebedeva IV, Dent P, Sarkar D, Fisher PB (July 2008). "Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 105 (28): 9763–8. Bibcode:2008PNAS..105.9763S. doi: 10.1073/pnas.0804089105 . PMC   2474541 . PMID   18599461.
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