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


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 kappaB (NFkappaB) 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-alpha induced NFkappaB 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 NFkappaB 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.
Gironella
M
M
Gastroenterology Department, Institut de Malalties Digestives, Hospital Clínic, Villarroel 170 08036 Barcelona, Spain.
Iovanna
J L
JL
Sans
M
M
Gil
F
F
Peñalva
M
M
Closa
D
D
Miquel
R
R
Piqué
J M
JM
Panés
J
J
D000704:Analysis of Variance; D000951:Antigens, Neoplasm / Q000097:blood* / Q000494:pharmacology; D001692:Biological Transport; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000097:blood / Q000276:immunology / Q000473:pathology; D003093:Colitis, Ulcerative / Q000097:blood / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000097:blood / Q000276:immunology / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000276:immunology / Q000473:pathology; D007378:Interleukins / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000097:blood*; D016328:NF-kappa B / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D019879:Paneth Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D007378:Interleukins; D037181:Lectins, C-Type; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha