T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease.
OBJECTIVE
Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn's disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD.


METHODS
CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5).


METHODS
(1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon gamma (IFN-gamma) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12.


RESULTS
(1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-gamma production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-gamma production and with augmentation of surface expressed IL-12 receptor beta2.


CONCLUSIONS
T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
K
K
Matsuoka
N
N
Inoue
T
T
Sato
S
S
Okamoto
T
T
Hisamatsu
Y
Y
Kishi
A
A
Sakuraba
O
O
Hitotsumatsu
H
H
Ogata
K
K
Koganei
T
T
Fukushima
T
T
Kanai
M
M
Watanabe
H
H
Ishii
T
T
Hibi
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003424:Crohn Disease / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000276:immunology; D000098815:T-bet Transcription Factor
D020382:Interleukin-18; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma