Development of inflammatory bowel disease in Long-Evans Cinnamon rats based on CD4+CD25+Foxp3+ regulatory T cell dysfunction.
A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN-gamma and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of the control Long-Evans Agouti rats through up-regulated expression of T-bet and phosphorylation of STAT-1 leading to NF-kappaB activation. In addition, the number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells of the thymus, MLNs, and lamina propria mononuclear cells from LEC rats was significantly reduced, comparing with that of the control rats. Moreover, bone marrow cell transfer from LEC rats into irradiated control rats revealed significantly reduced CD25(+)Foxp3(+) Treg cells in thymus, spleen, and MLNs compared with those from control rats. Indeed, adoptive transfer with T cells of MLNs, not spleen cells, from LEC rats into SCID mice resulted in the development of inflammatory lesions resembling the IBD-like lesions observed in LEC rats. These results indicate that the dysfunction of the regulatory system controlled by Treg cells may play a crucial role in the development of IBD-like lesions through up-regulated T-bet, STAT-1, and NF-kappaB activation of peripheral T cells in LEC rats.
Ishimaru
Naozumi
N
Department of Oral Molecular Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramotocho, Tokushima, Japan. ishimaru@dent.tokushima-u.ac.jp
Yamada
Akiko
A
Kohashi
Masayuki
M
Arakaki
Rieko
R
Takahashi
Tetsuyuki
T
Izumi
Keisuke
K
Hayashi
Yoshio
Y
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D020332:Rats, Inbred LEC; D011922:Rats, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D000098815:T-bet Transcription Factor
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor