Interleukin (IL)‐31 activates signal transducer and activator of transcription (STAT)‐1, STAT‐5 and extracellular signal‐regulated kinase 1/2 and down‐regulates IL‐12p40 production in activated human macrophages

BACKGROUND: Interleukin-31 is a cytokine expressed by activated T cells. A major function of IL-31 in atopic dermatitis (AD) is the induction of pruritus in the skin. We recently showed that IL-31 induces pro-inflammatory cytokines following staphylococcal exotoxins' stimulation in human macrophages. However, signalling pathways of IL-31 in activated human macrophages still remain unclear. The aim of the study was to investigate the signalling pathways of IL-31 receptor as well as functional effects of IL-31 in activated macrophages. METHODS: Human macrophages were prestimulated with staphylococcal exotoxins (SEB, α-toxin) to up-regulate the IL-31 receptor with and without IL-31. Phospho-signal transducer and activator of transcription (pSTAT) 1/3/5, phospho-extracellular signal-regulated kinase (ERK 1/2), β-actin as well as p21/WAF/Cip1 levels were determined by means of Western blot analysis. Interleukin-12p40, IL-12p70 and IL-23 secretions were assessed by using an enzyme-linked immunosorbent assay. RESULTS: Interleukin-31 strongly activated STAT-1 and 5 but not STAT-3 in human macrophages after up-regulation of IL-31 receptor with staphylococcal exotoxins. p21/WAF/Cip1 expression was induced by IL-31 in activated human macrophages. Furthermore, IL-31 down-regulated. IL-12p40 secretion via ERK 1/2 phosphorylation in human macrophages following up-regulation of IL-31 receptor with staphylococcal exotoxins. CONCLUSIONS: The T helper (Th) 2 cytokine IL-31 induces pro-inflammatory effects in activated human macrophages via STAT-1 and 5 phosphorylation. Interleukin-31-induced ERK 1/2 activation contributes to the underlying mechanism of Th1 cytokine IL-12 suppression in macrophages. This mechanism may be relevant in Th2 inflammatory responses and may help to develop therapeutic strategies in IL-31-associated diseases such as AD.