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 β and the cytokine-specific receptor subunit IL-31Rα, of which there are several isoforms. The latter can be classified as long or short isoforms with respect to their intracellular domain.

SOCS-1 and SOCS-3 inhibit IL-4 and IL-13 induced activation of Eotaxin-3/CCL26 gene expression in HEK293 cells.

Secretion of various chemokines including Eotaxin-3/CCL26 results in the attraction of eosinophils to sites of allergic inflammation. IL-4/IL-13-induced activation of the Eotaxin-3/CCL26 gene in human dermal fibroblasts was shown to be a STAT6-dependent process mediated by a single STAT6 binding motif located upstream of the transcription initiation site. The suppressors of cytokine signaling 1-3 (SOCS 1-3) are members of a recently discovered family of proteins acting as negative regulators of cytokine signaling.

IL-4 and IL-13 induce SOCS-1 gene expression in A549 cells by three functional STAT6-binding motifs located upstream of the transcription initiation site.

Proteins of the suppressors of cytokine signaling (SOCS) family have important functions as negative regulators of cytokine signaling. We show here that SOCS-1 expression can be induced in the human epithelial lung cell line A549 by IL-4 and IL-13. Analysis of reporter gene constructs under control of the SOCS-1 promoter provides evidence that IL-4- and IL-13-induced up-regulation is dependent on three IFN-gamma-activated sequence motifs of the sequence TTC(N)(4)GAA, which is known for binding STAT6.