Expression of IL-24 and IL-24 receptors in human wound tissues and the biological implications of IL-24 on keratinocytes

Interleukin (IL)-24, also known as melanoma differentiation-associated gene-7, is a cytokine initially identified from cancerous cells and expressed in a range of cell types. It is a regulator of cell differentiation, growth, and apoptosis, and a promising anticancer agent. IL-24 acts via its heterodimic receptors: the IL-20R1 and IL-20R2 complex and the IL-22R1 and IL-20R2 complex. There is limited information on the effect of IL-24 in wound healing. Human acute and chronic wound tissues were used to analyze the transcript levels and histological staining of IL-24 and the IL-24 receptors. The biological response of human keratinocytes to recombinant human IL-24 was evaluated using electric cell-substrate impedance sensing-based methods in conjunction with inhibitors to candidate signaling pathways. IL-24 significantly slowed the migration of keratinocytes (p = 0.01), with only a marginal effect on cellular adhesion. The inhibitory effect of IL-24 on migration was completed reversed following addition of an AKT inhibitor (p = 0.004) but not an SMAD3 pathway inhibitor. Human chronic wound tissues showed raised levels of both IL-24 (p = 0.003) and its receptor (p = 0.0305) compared with acute wound tissues. We conclude that IL-24 appears to promote wound chronicity via its inhibitory effect on the migratory behavior of human keratinocytes, mediated through an AKT-dependent pathway.