Gnotobiotic IL-10; NF-kappaB mice develop rapid and severe colitis following Campylobacter jejuni infection.
Limited information is available on the molecular mechanisms associated with Campylobacter jejuni (C. jejuni) induced food-borne diarrheal illnesses. In this study, we investigated the function of TLR/NF-kappaB signaling in C. jejuni induced pathogenesis using gnotobiotic IL-10(-/-); NF-kappaB(EGFP) mice. In vitro analysis showed that C. jejuni induced IkappaB phosphorylation, followed by enhanced NF-kappaB transcriptional activity and increased IL-6, MIP-2alpha and NOD2 mRNA accumulation in infected-mouse colonic epithelial cells CMT93. Importantly, these events were blocked by molecular delivery of an IkappaB inhibitor (Ad5IkappaBAA). NF-kappaB signalling was also important for C.jejuni-induced cytokine gene expression in bone marrow-derived dendritic cells. Importantly, C. jejuni associated IL-10(-/-); NF-kappaB(EGFP) mice developed mild (day 5) and severe (day 14) ulcerating colonic inflammation and bloody diarrhea as assessed by colonoscopy and histological analysis. Macroscopic analysis showed elevated EGFP expression indicating NF-kappaB activation throughout the colon of C. jejuni associated IL-10(-/-); NF-kappaB(EGFP) mice, while fluorescence microscopy revealed EGFP positive cells to be exclusively located in lamina propria mononuclear cells. Pharmacological NF-kappaB inhibition using Bay 11-7085 did not ameliorate C. jejuni induced colonic inflammation. Our findings indicate that C. jejuni induces rapid and severe intestinal inflammation in a susceptible host that correlates with enhanced NF-kappaB activity from lamina propria immune cells.
Lippert
Elisabeth
E
Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Karrasch
Thomas
T
Sun
Xiaolun
X
Allard
Brigitte
B
Herfarth
Hans H
HH
Threadgill
Deborah
D
Jobin
Christian
C
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002169:Campylobacter Infections / Q000382:microbiology*; D016123:Campylobacter jejuni / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D003092:Colitis / Q000235:genetics* / Q000378:metabolism* / Q000382:microbiology*; D003713:Dendritic Cells / Q000166:cytology; D005786:Gene Expression Regulation; D005856:Germ-Free Life / Q000235:genetics*; D020672:I-kappa B Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010766:Phosphorylation
D054426:Chemokine CXCL2; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha