Interleukin-25 inhibits interleukin-12 production and Th1 cell-driven inflammation in the gut.
OBJECTIVE
During the pathogenesis of Crohn's disease (CD), interleukin (IL)-12, a cytokine produced by mucosal CD14+ monocyte-like cells, promotes tissue-damaging T helper cell (Th) 1-mediated inflammation through mechanisms that are not fully understood. IL-25 promotes Th2 cell responses by activating major histocompatibility complex class II-positive non-T and non-B cells. Because Th1 and Th2 cells, and the cytokines they release, are often mutually antagonistic, we examined whether IL-25 affects IL-12 production or Th1 cell-mediated inflammation in the gut.


METHODS
Studies were performed using colonic samples from patients and mice with peptidoglycan (PGN)-, 2,4,6-trinitrobenzenesulphonic acid (TNBS)-, or oxazolone-induced colitis. IL-25 receptor (IL-25R) levels were evaluated in intestinal lamina propria mononuclear cells by flow cytometry, and IL-25 levels were measured by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Mucosal CD14+ cells from patients with CD were incubated with IL-25 and/or lipopolysaccharide or PGN. Mice were injected with IL-25, and some mice first received injections of an IL-13 blocking antibody. Cytokines were quantified by real-time polymerase chain reaction and enzyme-linked immunosorbent assay.


RESULTS
CD14+ cells from the mucosa of CD patients expressed IL-25R and responded to IL-25 by decreasing the synthesis of IL-12 and IL-23. IL-25 prevented PGN-induced colitis in mice. IL-25 induced IL-13 production in the colon, but IL-13 was not required for suppression of PGN colitis. IL-25 ameliorated TNBS- and oxazolone-colitis. Patients with CD or ulcerative colitis produced significantly less IL-25 compared with controls.


CONCLUSIONS
IL-25 inhibits CD14+ cell-derived cytokines and experimental colitis. IL-25 could be a useful treatment of CD and ulcerative colitis.
Caruso
Roberta
R
Department of Internal Medicine and Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University "Tor Vergata" of Rome, Rome, Italy.
Sarra
Massimiliano
M
Stolfi
Carmine
C
Rizzo
Angelamaria
A
Fina
Daniele
D
Fantini
Massimo Claudio
MC
Pallone
Francesco
F
MacDonald
Thomas T
TT
Monteleone
Giovanni
G
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis; D018664:Interleukin-12 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011336:Probability; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D018417:Th1 Cells / Q000276:immunology* / Q000502:physiology
D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D018664:Interleukin-12