title: Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis.
abstract: Nucleotide-binding oligomerization domain 1 (NOD1) fulfills important host-defense functions via its responses to a variety of gut pathogens. Recently, however, we showed that in acute pancreatitis caused by administration of cholecystokinin receptor (CCKR) agonist (cerulein) NOD1 also has a role in inflammation via its responses to gut commensal organisms. In the present study, we explored the long-term outcome of such NOD1 responsiveness in a new model of chronic pancreatitis induced by repeated administration of low doses of cerulein in combination with NOD1 ligand. We found that the development of chronic pancreatitis in this model requires intact NOD1 and type I IFN signaling and that such signaling mediates a macrophage-mediated inflammatory response that supports interleukin (IL)-33 production by acinar cells. The IL-33, in turn, has a necessary role in the induction of IL-13 and TGF-β1, factors causing the fibrotic reaction characteristic of chronic pancreatitis. Interestingly, the Th2 effects of IL-33 were attenuated by the concomitant type I IFN response since the inflammation was marked by clear increases in IFN-γ and TNF-α production but only marginal increases in IL-4 production. These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.|Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.|Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sadakane
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yagama
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Graduate School of Medicine, Osaka-sayama, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ezoe
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Graduate School of Medicine, Osaka-sayama, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000818:Animals; D002108:Ceruletide / Q000008:administration & dosage*; D003960:Diaminopimelic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33 / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D011949:Receptors, Cholecystokinin; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D003960:Diaminopimelic Acid; C034330:FK 156; D007371:Interferon-gamma; D002108:Ceruletide
references.citation: Lancet. 2011 Apr 2;377(9772):1184-97
references.pmid: 21397320
references.citation: Am J Pathol. 2005 Mar;166(3):721-8
references.pmid: 15743784
references.citation: Pancreas. 1989;4(5):565-71
references.pmid: 2478999
references.citation: Am J Pathol. 2012 Jun;180(6):2330-9
references.pmid: 22542450
references.citation: Gastroenterology. 1996 Jan;110(1):232-40
references.pmid: 8536862
references.citation: Lancet. 2008 Jan 12;371(9607):143-52
references.pmid: 18191686
references.citation: Annu Rev Physiol. 2007;69:249-69
references.pmid: 17059357
references.citation: Pancreas. 2012 Apr;41(3):353-7
references.pmid: 22415665
references.citation: J Pathol. 2015 Feb;235(3):478-89
references.pmid: 25348195
references.citation: PLoS One. 2013;8(2):e56308
references.pmid: 23457546
references.citation: J Vis Exp. 2013 Aug 13;(78):null
references.pmid: 23979477
references.citation: J Allergy Clin Immunol. 2014 Dec;134(6):1422-1432.e11
references.pmid: 24985397
references.citation: Gastroenterology. 2011 Dec;141(6):1972-5
references.pmid: 22033179
references.citation: Nat Rev Immunol. 2008 Apr;8(4):279-89
references.pmid: 18340345
references.citation: Immunity. 2012 Aug 24;37(2):326-38
references.pmid: 22902233
references.citation: Gastroenterology. 2013 May;144(5):1076-1085.e2
references.pmid: 23354015
references.citation: Nat Rev Immunol. 2006 Jan;6(1):9-20
references.pmid: 16493424
references.citation: PLoS One. 2014 Jan 20;9(1):e84072
references.pmid: 24465393
references.citation: Pancreatology. 2013 Mar-Apr;13(2):102-5
references.pmid: 23561965
references.citation: Am J Pathol. 2013 Sep;183(3):692-708
references.pmid: 23845568
references.citation: Curr Opin Immunol. 2014 Dec;31:31-7
references.pmid: 25278425
references.citation: J Immunol. 2013 Jul 1;191(1):283-92
references.pmid: 23733876
references.citation: Mucosal Immunol. 2008 Nov;1 Suppl 1:S24-7
references.pmid: 19079223
references.citation: Annu Rev Med. 2010;61:413-24
references.pmid: 20059346
references.citation: J Virol. 2014 Jan;88(1):164-75
references.pmid: 24131723
references.citation: Gastroenterology. 2011 Jul;141(1):358-69
references.pmid: 21439959
references.citation: Cytokine. 2012 Nov;60(2):514-21
references.pmid: 22819319
references.citation: J Clin Invest. 2014 Jul;124(7):3241-51
references.pmid: 24892809
references.citation: Mucosal Immunol. 2011 Sep;4(5):496-502
references.pmid: 21613987
references.citation: PLoS One. 2013;8(2):e56866
references.pmid: 23418608
references.citation: Cell. 2009 Jun 12;137(6):1100-11
references.pmid: 19524512
references.citation: J Immunol. 2015 Oct 1;195(7):3033-44
references.pmid: 26297761
references.citation: Mol Cell Biol. 2014 Feb;34(3):400-14
references.pmid: 24248596
references.citation: Science. 2012 Feb 24;335(6071):984-9
references.pmid: 22323740
references.citation: Immunity. 2012 Jul 27;37(1):171-86
references.pmid: 22749822
references.citation: Nat Rev Immunol. 2004 Jul;4(7):499-511
references.pmid: 15229469
references.citation: J Immunol. 2007 Mar 1;178(5):3126-33
references.pmid: 17312160
references.citation: J Clin Invest. 2010 May;120(5):1645-62
references.pmid: 20389019
references.citation: N Engl J Med. 1995 Jun 1;332(22):1482-90
references.pmid: 7739686
references.citation: Gastroenterology. 2011 Dec;141(6):2210-2217.e2
references.pmid: 21875495
references.citation: J Exp Med. 2012 Aug 27;209(9):1671-87
references.pmid: 22908323
references.citation: Immunity. 2013 Aug 22;39(2):357-71
references.pmid: 23954132
references.citation: Nat Immunol. 2011 Nov;12(11):1045-54
references.pmid: 21946417
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Oct;299(4):G821-32
references.pmid: 20689058
references.citation: J Immunol. 2015 Apr 15;194(8):3583-93
references.pmid: 25780046
references.citation: Curr Opin Gastroenterol. 2011 Sep;27(5):444-51
references.pmid: 21844752
references.citation: Gastroenterology. 2001 Feb;120(3):682-707
references.pmid: 11179244
references.citation: Am J Pathol. 2009 Nov;175(5):2023-33
references.pmid: 19808647