Interleukin 24 (IL-24) is a protein in theinterleukin family, a type ofcytokine signaling molecule in the immune system. In humans, thisprotein is encoded by theIL24gene.
IL-24 is acytokine belonging to theIL-10 family of cytokines that signals through twoheterodimeric 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 atumour suppressing protein. IL-24 appears to control cell survival andproliferation by inducing rapid activation of particulartranscription factors calledSTAT1 andSTAT3. This cytokine is predominantly released by activatedmonocytes,macrophages andT helper 2 (Th2) cells[5] and acts on skin, lung, and reproductive tissues. IL-24 performs important roles in wound healing,arthritis,psoriasis andcancer.[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 onchromosome 1 in humans.[11]
The structure of IL-24 has been found throughcrystallization by fusing a flexiblelinker with aligand to its two receptors, IL-22R1 and IL-20R2. The structure revealed that there is a lack ofdisulfides, 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 withsequence homology between species including yeast, dog, cat, monkey and cow. It is located on chromosome 1q32-33 in humans along with several otherIL-10 cytokine family gene members. IL-24 encompasses sevenexons and sixintrons. ThecDNA of IL-24 is 1,718base pairs in length and encodes a protein of 206amino 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 ofsplice 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]
IL-24 functions as acytokine (at low concentrations). Its normal physiological role is connected with wound healing (In normal skin cells, it suppresskeratinocyte proliferation during wound healing[15]), and protection against diseases caused by bacteria (for exampleMycobacterim tuberculosis,Salmonella typhimurium,Pseudomonas aeruginosa). It is also important inautoimmune diseases such aspsoriasis,rheumatoid arthritis or spondyloarthropathy.
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 includesIL-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 theircytoplasmic domains.[16]
Although it belongs to the same group of cytokines asIL-10, it has different effect on the immune system. IL-10 is a suppressive cytokine that suppressesinflammation while also maintaining immunomodulatory functions. Beside the normal physiological roles, IL-24 inhibits tumor growth, invasion,metastasis andangiogenesis.[17]
IL-24 can be produced bymyeloid cells (in response to microbial products throughTLRs),lymphoid cells, andepithelial cells in response to cytokine stimulation. IL-24 can also dampen the first rounds ofCD8 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]
IL-24 is an immunomodulatorycytokine which can also display broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition ofangiogenesis,sensitization tochemotherapy, and induction of cancer-specificapoptosis. Given its ubiquitous apoptotic effect onmalignant 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 induceapoptosis 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 anER stress-mediated pathway as well as byROS 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 andceramide), another possibility is that IL-24 is able to target a molecule that only triggersapoptosis 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 toxicautophagy 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 includeTNF-α,IFN-gamma, andIL-1, which induce apoptosis.[21] IL-24 also inhibits cancer by blockingVEGF andTGF-alpha activities through inhibition ofSrc, 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]
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