Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis.
The intracellular sensor NOD1 has important host-defense functions relating to a variety of pathogens. Here, we showed that this molecule also participates in the induction of a noninfectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity, we induced pancreatitis by simultaneous administration of a low dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intrapancreatic influx of CCR2(+) inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-κB and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable noninfectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Yoshihisa
Y
Tsuji
Tomohiro
T
Watanabe
Masatoshi
M
Kudo
Hidenori
H
Arai
Warren
W
Strober
Tsutomu
T
Chiba
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000009:adverse effects; D061354:Acinar Cells / Q000276:immunology*; D000818:Animals; D001419:Bacteria / Q000276:immunology; D002108:Ceruletide / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology; D003960:Diaminopimelic Acid / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000276:immunology* / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology* / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology*; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D054390:Receptors, CCR2; D050796:STAT3 Transcription Factor; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D003960:Diaminopimelic Acid; C034330:FK 156; D002108:Ceruletide