Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes.
T cell-mediated immune responses are implicated in the pathogenesis of a variety of liver disorders; however, the underlying mechanism remains obscure. Con A injection is a widely accepted mouse model to study T cell-mediated liver injury, in which STAT6 is rapidly activated. Disruption of the IL-4 and STAT6 gene by way of genetic knockout abolishes Con A-mediated liver injury without affecting IFN-gamma/STAT1, IL-6/STAT3, or TNF-alpha/NF-kappaB signaling or affecting NKT cell activation. Infiltration of neutrophils and eosinophils in Con A-induced hepatitis is markedly suppressed in IL-4 (-/-) and STAT6(-/-) mice compared with wild-type mice. IL-4 treatment induces expression of eotaxins in hepatocytes and sinusoidal endothelial cells isolated from wild-type mice but not from STAT6(-/-) mice. Con A injection induces expression of eotaxins in the liver and elevates serum levels of IL-5 and eotaxins; such induction is markedly attenuated in IL-4(-/-) and STAT6(-/-) mice. Finally, eotaxin blockade attenuates Con A-induced liver injury and leukocyte infiltration. Taken together, these findings suggest that IL-4/STAT6 plays a critical role in Con A-induced hepatitis, via enhancing expression of eotaxins in hepatocytes and sinusoidal endothelial cells, and induces IL-5 expression, thereby facilitating recruitment of eosinophils and neutrophils into the liver and resulting in hepatitis.
Jaruga
Barbara
B
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Hong
Feng
F
Sun
Rui
R
Radaeva
Svetlana
S
Gao
Bin
B
D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D003208:Concanavalin A / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000502:physiology; D004804:Eosinophils / Q000473:pathology; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007106:Immune Sera / Q000008:administration & dosage; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology; D007962:Leukocytes / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D007106:Immune Sera; D015848:Interleukin-5; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma