title: 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.
abstract: 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.
authors.affiliation: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. sadafkasraie@gmail.com
authors.forename: S
authors.initials: S
authors.lastname: Kasraie
authors.forename: M
authors.initials: M
authors.lastname: Niebuhr
authors.forename: T
authors.initials: T
authors.lastname: Werfel
mesh_terms: D001427:Bacterial Toxins / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015536:Down-Regulation; D004768:Enterotoxins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006460:Hemolysin Proteins / Q000276:immunology; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D015415:Biomarkers; D004768:Enterotoxins; D006460:Hemolysin Proteins; C502187:IL31 protein, human; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C021091:staphylococcal alpha-toxin; C031818:enterotoxin B, staphylococcal; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3