title: Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis.
abstract: OBJECTIVE
  The soluble hematopoietin receptor Epstein-Barr virus-induced protein (EBI)-3 is an immune regulator that has been associated with the pathogenesis of inflammatory bowel disease. However, the concept that EBI3 is part of an interleukin (IL)-27 heterodimer that mediates chronic inflammatory and autoimmune diseases has been challenged by the description of IL-35, a bioactive cytokine comprising EBI3 and IL-12 p35. We investigated the roles of IL-27 and IL-35 in chronic inflammation of the intestine.
  
  
  METHODS
  We analyzed EBI3-deficient mice and IL-27p28-deficient mice with spontaneous or T-cell transfer-induced colitis and compared outcomes with wild-type mice (controls). We constructed vectors that express EBI3 covalently linked to the IL-12p35 chain (recombinant [r]IL-35).
  
  
  RESULTS
  Intestines of EBI3-deficient mice had increased pathologic features of colitis, compared with IL-27p28-deficient or control mice; they also had shorter survival times, indicating that IL-35, rather than IL-27, protects the intestine from immune responses in mice. The mucosa of EBI3-deficient mice accumulated subsets of activated CD4+ T cells that produced T-helper (Th)1 and Th17 cytokines. Adoptive transfer of these T cells induced colitis in RAG-deficient mice. The rIL-35 significantly reduced the development of several forms of experimental colitis and reduced levels of markers of Th1 and Th17 cells.
  
  
  CONCLUSIONS
  IL-35 controls the development of T-cell-dependent colitis in mice. It might be developed as a therapeutic target for patients with chronic intestinal inflammation.
authors.affiliation: Medical Department 1, University of Erlangen-Nuremberg, Erlangen, Germany. Stefan.Wirtz@uk-erlangen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Billmeier
authors.forename: Tamuna
authors.initials: T
authors.lastname: Mchedlidze
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018928:Immunity, Mucosal / Q000187:drug effects / Q000502:physiology*; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010641:Phenotype; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D018417:Th1 Cells / Q000473:pathology / Q000502:physiology; D058504:Th17 Cells / Q000473:pathology / Q000502:physiology; D015854:Up-Regulation
chemical_list: C499601:Ebi3 protein, mouse; D053765:Interleukin-12 Subunit p35; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; C569375:interleukin-35, mouse