PDF《bowel disease》

ARTICLE Received

12 Jul

2016 | Accepted

24 Mar

2017 | Published

31 May

2017 Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of in?ammatory bowel disease Magali de Bruyn1,2,*, Christine Breynaert3,*, Ingrid Arijs2,4, Gert De Hertogh5, Karel Geboes5, Greet Thijs1, Gianluca Matteoli2, Jialiang Hu6, Jo Van Damme7, Bernd Arnold8, Marc Ferrante2,9, Se ?verine Vermeire2,9, Gert Van Assche2,9 &

Ghislain Opdenakker1 One third of patients with in?ammatory bowel disease (IBD) inadequately respond to anti-TNF treatment and preclinical data suggest that matrix metalloproteinase-9 (MMP-9) is a novel therapeutic target.

Here we show that IBD clinical and histopathological parameters found in wild type mice challenged with three different models of colitis, acute and chronic dextran sodium sulphate (DSS), and acute 2,4,6-trinitrobenzenesulfonic acid-induced colitis are not attenuated in MMP-9 knockout mice. We ?nd similar colonic gene expression pro?les in wild type and MMP-9 knockout mice in control and acute DSS conditions with the exception of eleven genes involved in antimicrobial response during colitis. Parameters of chronic colitis are similar in wild type and MMP-9 knockout mice. Pharmacological inhibition of MMP-9 with bio-active peptides does not improve DSS colitis. We suggest that MMP-9 upregulation is a consequence rather than a cause of intestinal in?ammation and we question whether MMP-9 represents a disease target in IBD. DOI: 10.1038/ncomms15384 OPEN

1 Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium.

2 Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven 3000, Belgium.

3 Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.

4 Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium.

5 Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium.

6 Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.

7 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium.

8 Department of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

9 University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven 3000, Belgium. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to G.O. (email: [email protected]). NATURE COMMUNICATIONS | 8:15384 | DOI: 10.1038/ncomms15384 | www.nature.com/naturecommunications

1 I n?ammatory bowel diseases (IBD), including Crohn'

s disease (CD) and ulcerative colitis (UC), are chronic relapsing- remitting diseases of the gastrointestinal tract1. Patients present with (bloody) diarrhoea, abdominal cramping, fever, fatigue and unintended weight loss. Both UC and CD are common multifactorial diseases that cause enormous patient discomfort and high healthcare costs for the society. The incidence and prevalence of IBD are increasing worldwide, including in developing countries2. Despite extensive research, the etiopathogenesis of IBD is not yet fully understood. It is thought that an abnormal immune response is elicited towards the luminal microbiota in a genetically susceptible host1. The introduction of anti-tumour necrosis factor biologicals more than