Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage
- 1Department of Inflammation, Immunex Corporation, 51 University Street, Seattle, WA 98101, USA
- 2Department of Molecular Biology, Immunex Corporation, 51 University Street, Seattle, WA 98101, USA
- Correspondence to:
Dr J L Viney, Immunex Corporation, 51 University Street, Seattle, WA 98101, USA;
- Accepted 18 September 2001
Background and aims: Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD.
Methods: Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays.
Results: IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD.
Conclusions: IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.
- CD, Crohn's disease
- UC, ulcerative colitis
- DSS, dextran sulphate sodium
- IBD, inflammatory bowel disease
- IL, interleukin
- IL-18bp, interleukin 18 binding protein
- IL-1ra, interleukin 1 receptor antagonist
- ICE, interleukin 1 converting enzyme
- IFN-γ, interferon γ
- PBS, phosphate buffered saline
- RPA, RNase protection assay
- MMP, matrix metalloprotease
- TIMP, tissue inhibitor of MMPs
- MLN, mesenteric lymph node
- TNF-α, tumour necrosis factor α
- HuIgG, human IgG
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
Conflict of interest: All authors are employees of Immunex Corporation, Seattle, Washington, USA