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Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice.

Abstract：

BACKGROUND AND PURPOSE:Intestinal mucositis is a common side-effect of irinotecan-based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL-18 is up-regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL-18 in the pathogenesis of irinotecan-induced intestinal mucositis. EXPERIMENTAL APPROACH:Wild type (WT), IL-18 or caspase-1 knockout mice were treated with either saline or irinotecan (60 mg·kg⁻¹ per 4 days, i.p.) or the IL-18 binding protein (IL-18bp, 10 mg·kg⁻¹) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL-18 expression. KEY RESULTS:Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL-18 expression in WT mice compared with saline treatment. The IL-18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase-1 knockout and IL-18 knockout mice, and in IL-18bp-treated WT mice. Furthermore, the Survival of irinotecan-treated mice was increased and iNOS immunoexpression and IL-18 production prevented in IL-18 knockout mice. CONCLUSIONS AND IMPLICATIONS:Targeting IL-18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Lima-Júnior RC,Freitas HC,Wong DV,Wanderley CW,Nunes LG,Leite LL,Miranda SP,Souza MH,Brito GA,Magalhães PJ,Teixeira MM,Cunha FQ,Ribeiro RA

doi

10.1111/bph.12584

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

2335-50

issue

eissn

0007-1188

issn

1476-5381

journal_volume

171

pub_type

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Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice.