Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.
Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.
Siegmund
B
B
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA. Britta.Siegmund@UCHSC.edu
Fantuzzi
G
G
Rieder
F
F
Gamboni-Robertson
F
F
Lehr
H A
HA
Hartmann
G
G
Dinarello
C A
CA
Endres
S
S
Eigler
A
A
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007106:Immune Sera; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D016264:Dextran Sulfate