Characterization of cecal gene expression in a differentially susceptible mouse model of bacterial-induced inflammatory bowel disease.
BACKGROUND
A/JCr mice develop typhlitis in response to Helicobacter hepaticus infection, whereas C57BL/6 mice coexist with this bacterium in a "commensal" relationship and do not develop disease even during prolonged colonization.


METHODS
To determine mechanisms that control this balance between responsiveness and nonresponsiveness, the mucosal response of A/JCr and C57BL/6 mice to acute H. hepaticus colonization was evaluated using genome-wide profiling. Transcription levels for a subset of gene discoveries were then evaluated longitudinally by semiquantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) to identify changes in gene expression that occur during progression from the acute to chronic phase of colonization. To determine whether chronic mucosal inflammation in A/JCr mice was mediated through a Th1 mechanism, as was inferred from the gene expression data, mice with typhlitis were treated with neutralizing antibody targeting IL-12/23p40 or IFN-gamma and the response to treatment was determined by cecal lesion severity and transcription of disease-related genes.


RESULTS
A/JCr mice had a biphasic expression of proinflammatory genes that corresponded with the acute and chronic phases of disease. In contrast, C57BL/6 mice exhibited a less robust acute transcriptional response that waned by day 30 postinoculation. Sustained upregulation of proinflammatory signals and responsiveness to anti-IL-12/23p40 and anti-IFN-gamma antibody suggests that inflammation in A/JCr mice was mediated through a Th1 mechanism. Prolonged upregulation of SOCS3 during the acute response to colonization suggests that C57BL/6 mice maintain mucosal homeostasis, at least in part by attenuating responsiveness to cytokine signaling.


CONCLUSIONS
Collectively, these findings provide a foundation for understanding the immunological mechanisms that confer resistance or susceptibility to H. hepaticus-induced typhlitis.
Myles
Matthew H
MH
Research Animal Diagnostic Laboratory, Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri 65211, USA. mylesm@missouri.edu
Dieckgraefe
Brian K
BK
Criley
Jennifer M
JM
Franklin
Craig L
CL
D000818:Animals; D000911:Antibodies, Monoclonal; D002432:Cecum / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D016481:Helicobacter Infections / Q000150:complications; D044923:Helicobacter hepaticus; D018928:Immunity, Mucosal / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D053706:Typhlitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D000911:Antibodies, Monoclonal; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins