Mechanism of Action and Applications of Interleukin 24 in Immunotherapy

Abstract

Interleukin 24 (IL-24) is an important pleiotropic immunoregulatory cytokine, whose gene is located in human chromosome 1q32-33. IL-24's signaling pathways have diverse biological functions related to cell differentiation, proliferation, development, apoptosis, and inflammation, placing it at the center of an active area of research. IL-24 is well known for its apoptotic effect in cancer cells while having no such effect on normal cells. IL-24 can also be secreted by both immune and non-immune cells. Downstream effects of IL-24, after binding to the IL-20 receptor, can occur dependently or independently of the JAK/STAT signal transduction pathway, which is classically involved in cytokine-mediated activities. After exogenous addition of IL-24, apoptosis is induced in tumor cells independently of the JAK/STAT pathway. We have shown that IL-24 binds to Sigma 1 Receptor and this event induces endoplasmic reticulum stress, calcium mobilization, reactive oxygen species generation, p38MAPK activity, and ceramide production. Here we review IL-24's role in autoimmunity, infectious disease response, wound repair, and vascular disease. Detailed understanding of the pleiotropic roles of IL-24 signaling can assist in the selection of more accurate therapeutic approaches, as well as targeting of appropriate cell types in treatment strategy development, and ultimately achieve desired therapeutic effects.

Keywords: IL-24; Sigma 1 Receptor; cancer; endoplasmic reticulum (ER) stress; inflammatory disease.

Figure 1

Three-dimensional structure of hIL-24 with its IL-20R receptor. Using the known crystal structures of IL-19, IL-22, and IL-20, a stable three-dimensional structure of human IL-24 (hIL-24) was obtained using computer modeling. When bound to each other, IL-20R receptor chain (yellow and pink) and hIL-24 share eight hydrogen bonds and 102 non-bonded interactions similar to IL-20 and IL-20R receptor chain [74].