Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease.
OBJECTIVE
Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still unclear.


METHODS
Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn's disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon gamma (IFNgamma) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1beta plus IL6, transforming growth factor beta1 (TGFbeta1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.


RESULTS
IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNgamma. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNgamma production and decreased IL17 production. TGFbeta1 dose-dependently decreased IFNgamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production.


CONCLUSIONS
Our findings support a role for IL12, TGFbeta and IL21 in modulating IL17/IFNgamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNgamma antibodies in clinical trials of Crohn's disease.
Rovedatti
L
L
Institute of Cell and Molecular Science, London School of Medicine and Dentistry, London E1 2AT, UK.
Kudo
T
T
Biancheri
P
P
Sarra
M
M
Knowles
C H
CH
Rampton
D S
DS
Corazza
G R
GR
Monteleone
G
G
Di Sabatino
A
A
Macdonald
T T
TT
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D016326:Extracellular Matrix Proteins / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000276:immunology; D008875:Middle Aged; D009924:Organ Culture Techniques; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D055815:Young Adult; D000099222:betaIG-H3 Protein
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020381:Interleukin-17; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein