CDB15:0000897 IL24 — IL20RA

ABSTRACT: Interleukin 24 (IL-24) encodes a secreted protein that exhibits significant homology to the interleukin 10 (IL-10) family of cytokines. Here we show that the human IL-24 is secreted by activated peripheral blood mononuclear cells and is the ligand for two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. The latter is also the receptor for IL-20. COS cells transfected with either IL-24 receptor heterodimers bind the ligand with similar saturation kinetics. IL-24 binding to either its endogenous receptors on human keratinocytes or to ectopically expressed receptors on baby hamster kidney cells leads to activation of the signal transducers and activators of transcription. Taken together, these results provide compelling evidence for IL-24 being the fourth member of IL-10 family of cytokines to which their specific receptors have been identified.

ABSTRACT: Cytokines that signal through Class II receptors form a distinct family that includes the interferons and interleukin 10 (IL-10). Recent identification of several IL-10 homologs has defined a cytokine subfamily that includes AK155, IL-19, IL-20, IL-22, and IL-24. Within this subfamily, IL-19, IL-20, and IL-24 exhibit substantial sharing of receptor complexes; all three are capable of signaling through IL-20RA/IL-20RB, and IL-20 and IL-24 both can also use IL-22R/IL-20RB. However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24. To more fully elucidate their interactions with the receptor complexes, we have performed a series of in vitro assays. Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.

ABSTRACT: IL-20 and IL-24 share two different heterodimeric receptors consisting of either IL-20R1 or IL-22R1 and a common IL-20R2 subunit, whereas IL-22 signals through IL-22R1/IL-10R2. However, until now, only IL-20 and IL-22 have been proven to play important roles in vivo in the epidermis where all four receptor subunits are expressed. In this study, we show that IL-24 transgenic mice manifest many similar phenotypes to that of IL-20 and IL-22, including neonatal lethality, epidermal hyperplasia, and abnormality in keratinocyte differentiation. These results support a largely redundant role in epidermal functions for IL-20, IL-22, and IL-24, which seem to be IL-22R1 dependent. Moreover, we show that IL-24 transgenic mice exhibit infiltrating macrophages in the dermis with concomitant increases in MCP-1 production from both keratinocytes in the epidermis and immune infiltrates in the adjacent dermal layer below. Furthermore, we demonstrate that the homodimeric IL-20R2 soluble receptor is a potent blocker for IL-24 and can be used to further dissect the crosstalk among the IL-20 family of cytokines in normal development as well as in autoimmune diseases.