IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD.
Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of T(h)1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4(+) T cell IFN-gamma production through effects on Tbet, a key T(h)1 transcription factor. We also found that its ability to suppress T(h)2 responses, which was clearly evident in helminth-infected IL-10-/-IL-27R-/- mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote T(h)1-type and suppress T(h)2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.
Villarino
Alejandro V
AV
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA. alejandro.villarino@ucsf.edu
Artis
David
D
Bezbradica
Jelena S
JS
Miller
Omer
O
Saris
Christiaan J M
CJ
Joyce
Sebastian
S
Hunter
Christopher A
CA
D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000276:immunology; D014257:Trichuriasis / Q000276:immunology / Q000503:physiopathology; D014258:Trichuris; D000098815:T-bet Transcription Factor
D016207:Cytokines; C484747:Il27ra protein, mouse; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016753:Interleukin-10