Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease

Meritxell Gironella ¹, Juan L Iovanna ², Miquel Sans ¹, Félix Gil ¹, Mireia Peñalva ¹, Daniel Closa ³, Rosa Miquel ¹, Josep M Piqué ¹ and Julián Panés ^1*

¹ Hospital Clínic de Barcelona, Spain
² INSERM, France
³ IIBB-CSIC, Spain

^* To whom correspondence should be addressed. E-mail: jpanes{at}clinic.ub.es.

Accepted 26 April 2005

Abstract

Background and aims: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterize PAP production in IBD and the effects of PAP on inflammation.

Patients and methods: Serum PAP levels were determined in healthy controls (n=29), inflammatory controls (n=14) and IBD patients (n=171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on NF-B activation, pro- inflammatory cytokine production and endothelial adhesion molecule expression were also analyzed ex-vivo.

Results: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histologic severity of inflammatory lesions. PAP localized to colonic Paneth cells. Incubation of mucosa from active Crohn's disease (CD) with PAP dose-dependently reduced pro-inflammatory cytokines secretion. PAP prevented TNF-& [alpha]-{induced NF-B-activation in monocytic, epithelial, and endothelial cells and reduced pro- inflammatory cytokine mRNA levels and adhesion molecule expression.

Conclusions: PAP is synthesized by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NF-B activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.

Keywords: inflammatory bowel disease, NF-kappa B, pancreatitis associated protein, paneth cells

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