IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice

Guabiraba Brito, R. et al. (2014) IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice. Mucosal Immunology, 7(5), pp. 1079-1093. (doi: 10.1038/mi.2013.124)

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Abstract

Intestinal damage and severe diarrhea are serious side effects of cancer chemotherapy and constrain the usage of most such therapies. Here we show that interleukin-33 (IL-33) mediates the severe intestinal mucositis in mice treated with irinotecan (CPT-11), a commonly used cancer chemotherapeutic agent. Systemic CPT-11 administration led to severe mucosal damage, diarrhea, and body weight loss concomitant with the induction of IL-33 in the small intestine (SI). This mucositis was markedly reduced in mice deficient in the IL-33R (ST2−/−). Moreover, recombinant IL-33 exacerbated the CPT-11-induced mucositis, whereas IL-33 blockade with anti-IL-33 antibody or soluble ST2 markedly attenuated the disease. CPT-11 treatment increased neutrophil accumulation in the SI and adhesion to mesenteric veins. Supernatants from SI explants treated with CPT-11 enhanced transmigration of neutrophils in vitro in an IL-33-, CXCL1/2-, and CXCR2-dependent manner. Importantly, IL-33 blockade reduced mucositis and enabled prolonged CPT-11 treatment of ectopic CT26 colon carcinoma, leading to a beneficial outcome of the chemotherapy. These results suggest that inhibition of the IL-33/ST2 pathway may represent a novel approach to limit mucositis and thus improve the effectiveness of chemotherapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo and Besnard, Dr Anne-Gaelle and Guabiraba Brito, Dr Rodrigo and Graham, Professor Gerard
Authors: Guabiraba Brito, R., Besnard, A.-G., Menezes, G.B., Secher, T., Jabir, M.S., Amaral, S.S., Braun, H., Lima-Junior, R.C.P., Ribeiro, R.A., Cunha, F.Q., Teixeira, M.M., Beyaert, R., Graham, G.J., and Liew, F.Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Mucosal Immunology
Publisher:Nature Publishing Group
ISSN:1933-0219
ISSN (Online):1935-3456

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