Interleukin 24
Interleukin 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 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 cells and acts on skin, lung, and reproductive tissues. IL-24 performs important roles in wound healing, arthritis, psoriasis and cancer. Several studies have shown that cell death occurs in cancer cells/cell lines following exposure to IL-24. The gene for IL-24 is located on chromosome 1 in humans.
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.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. The signal peptide in IL-24 is two times the length as in other related human cytokines, and the predicted molecular mass of IL-24 monomer is 18.3 kDa.
Function
IL-24 functions as a cytokine. Its normal physiological role is connected with wound healing, protection against diseases caused by bacteria. It is also important in autoimmune diseases such as psoriasis, rheumatoid arthritis or spondyloarthropathy.IL-24's Role in the Jak/STAT Pathway">JAK-STAT signaling pathway">Jak/STAT Pathway
IL-24 carries its functions through two types of membrane receptors with simultaneous activation of the JAK/signal transducer and activator of transcription pathway within their cytoplasmic domains. 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, simultaneous activation of the JAK/signal transducer and activator of transcription pathway within their cytoplasmic domains.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.
Production of IL-24 by Different Cells
IL-24 can be produced by myeloid cells, 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.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.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.
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, 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.
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.
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. 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. IL-24 also induces apoptosis By inducing more stress on the endoplasmic reticulum.