Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis.
NKT cells are highly enriched within the liver. On activation NKT cells rapidly release large quantities of different cytokines which subsequently activate, recruit, or modulate cells important for the development of hepatic inflammation. Recently, it has been demonstrated that NKT cells can also produce interleukin-17 (IL-17), a proinflammatory cytokine that is also known to have diverse immunoregulatory effects. The role played by IL-17 in hepatic inflammation is unclear. Here we show that during α-galactosylceramide (αGalCer)-induced hepatitis in mice, a model of hepatitis driven by specific activation of the innate immune system via NKT cells within the liver, NK1.1+ and CD4+ iNKT cells rapidly produce IL-17 and are the main IL-17-producing cells within the liver. Administration of IL-17 neutralizing monoclonal antibodies before αGalCer injection significantly exacerbated hepatitis, in association with a significant increase in hepatic neutrophil and proinflammatory monocyte (ie, producing IL-12, tumor necrosis factor-α) recruitment, and increased hepatic mRNA and protein expression for the relevant neutrophil and monocyte chemokines CXCL5/LIX and CCL2/MCP-1, respectively. In contrast, administration of exogenous recombinant murine IL-17 before α-GalCer injection ameliorated hepatitis and inhibited the recruitment of inflammatory monocytes into the liver. Our results demonstrate that hepatic iNKT cells specifically activated with α-GalCer rapidly produce IL-17, and IL-17 produced after α-GalCer administration inhibits the development of hepatitis.
Wondimu
Zenebech
Z
Immunology Research Group, Health Sciences Center, University of Calgary, 3330 Hospital Dr., NW, Calgary, Alberta, Canada, T2N 4N1.
Santodomingo-Garzon
Tania
T
Le
Tai
T
Swain
Mark G
MG
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology
D018925:Chemokines; D005699:Galactosylceramides; D020381:Interleukin-17; D016209:Interleukin-8; C493154:alpha-galactosylceramide