Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3)

Interleukin-31 (IL-31) is a T helper type 2 cell-derived cytokine tightly associated with inflammatory skin disorders. IL-31-induced signaling is mediated by a receptor complex composed of oncostatin M receptor beta and the cytokine-specific receptor subunit IL-31R alpha, of which there are several isoforms. The latter can be classified as long or short isoforms with respect to their intracellular domain. At present, the signaling capabilities of the different isoforms remain inchoately understood, and potential mechanisms involved in negative regulation of IL-31R alpha signaling have so far not been studied in detail. Here, we show that both the long and short isoforms of IL-31R alpha are capable of inducing STAT signaling. However, the presence of a functional JAK-binding box within IL-31R alpha is an essential prerequisite for functional IL-31-mediated STAT3 signaling. Moreover, both the long and short isoforms require on costatin M receptor beta for their activity. We also show that IL-31 induces expression of four suppressor of cytokine signaling family members and provide evidence that SOCS3 acts as a potent feedback inhibitor of IL-31-induced signaling. Taken together, this study identifies crucial requirements for IL-31 signaling and shows its counter-regulation by SOCS3.