Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice.
OBJECTIVE
Interleukin (IL) 18 has proinflammatory effects. IL-18 plays a pivotal role in Th1 responses, but its proinflammatory activities extend beyond Th1 cells, including macrophages and production of tumor necrosis factor (TNF) alpha and IL-1beta. IL-18 is up-regulated in colonic specimens of patients with Crohn's disease. The goal of this study was to evaluate the role of IL-18.


METHODS
Activity of IL-18 was neutralized using recombinant human IL-18 binding protein isoform a (rhIL-18BPa) in trinitrobenzene sulfonic acid (TNBS)-induced colitis.


RESULTS
Mice treated daily with rhIL-18BPa (8 mg/kg) had significant reductions in clinical score, body weight loss, and colon weight increase compared with saline-treated mice. Histologic analysis showed that rhIL-18BPa-treated mice developed only mild colitis without signs of ulceration, with a mean total score of 9.8 +/- 1.3 points compared with 15.9 +/- 1.1 points observed in saline-treated mice with colitis. Analysis of cytokine levels in colon homogenates showed a significant decrease in TNF-alpha, IL-6, and IL-1beta after rhIL-18BPa treatment but no effect on interferon gamma. The therapeutic potential of rhIL-18BPa treatment was confirmed in TNBS mice that were treated only on days 8 and 9 after the start of the experiment. In these mice, significant reductions in total colitis score and colon weight were also observed.


CONCLUSIONS
These findings show that inhibition of rhIL-18BPa bioactivity, via rhIL-18BPa, may be beneficial for the treatment of IBD.
Ten Hove
T
T
Laboratory of Experimental Internal Medicine G2-136, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Corbaz
A
A
Amitai
H
H
Aloni
S
S
Belzer
I
I
Graber
P
P
Drillenburg
P
P
van Deventer
S J
SJ
Chvatchko
Y
Y
Te Velde
A A
AA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020033:Protein Isoforms / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C118370:interleukin-18 binding protein; D014302:Trinitrobenzenesulfonic Acid