title: Interleukin 37 expression protects mice from colitis.
abstract: IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.
authors.affiliation: Department of Medicine, Section of Pediatric Gastroenterology, Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Eóin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Masterson
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Martine
authors.initials: M
authors.lastname: McManus
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Colm B
authors.initials: CB
authors.lastname: Collins
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Nold
authors.forename: Claudia
authors.initials: C
authors.lastname: Nold-Petry
authors.forename: Philip
authors.initials: P
authors.lastname: Bufler
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Jesús
authors.initials: J
authors.lastname: Rivera-Nieves
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D005434:Flow Cytometry; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C508587:IL37 protein, human; D007375:Interleukin-1; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate