INFLAMMATORY BOWEL DISEASE

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

M Gironella¹, J L Iovanna², M Sans³, F Gil³, M Peñalva³, D Closa⁴, R Miquel⁵, J M Piqué³, J Panés³

¹ Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Barcelona, Spain, and U624, Centre de Recherche INSERM, Marseille, France
² U624, Centre de Recherche INSERM, Marseille, France
³ Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Barcelona, Spain
⁴ Department of Experimental Pathology, IIBB-CSIC, Barcelona, Spain
⁵ Department of Pathology, Hospital Clínic, Barcelona, Spain

Correspondence to:
Dr J Panés
Gastroenterology Department, Hospital Clínic, Villarroel 170 08036 Barcelona, Spain; panes{at}ub.edu

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 characterise 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 nuclear factor B (NFB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed 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 histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn’s disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF- induced NFB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression.

Conclusions: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFB 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.

Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis; PAP, pancreatitis associated protein; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; HUVEC, human umbilical vein endothelial cells; IL, interleukin; IFN-, interferon ; TNF-, tumour necrosis factor ; NFB, nuclear factor B; RT-PCR, reverse transcription-polymerase chain reaction

Keywords: pancreatitis associated protein; inflammatory bowel diseases; nuclear factor B; inflammation; Paneth cells

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