Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.
We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.
Wirtz
S
S
Laboratory of Immunology, I. Medical Clinic, University of Mainz, Germany.
Finotto
S
S
Kanzler
S
S
Lohse
A W
AW
Blessing
M
M
Lehr
H A
HA
Galle
P R
PR
Neurath
M F
MF
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D006241:Haptens / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*