Activation of CD11b+ Kupffer cells/macrophages as a common cause for exacerbation of TNF/Fas-ligand-dependent hepatitis in hypercholesterolemic mice.
We have reported that the mouse hepatic injury induced by either α-galactosylceramide (α-GalCer) or bacterial DNA motifs (CpG-ODN) is mediated by the TNF/NKT cell/Fas-ligand (FasL) pathway. In addition, F4/80(+) Kupffer cells can be subclassified into CD68(+) subset with a phagocytosing capacity and CD11b(+) subset with a TNF-producing capacity. CD11b(+) subset increase if mice are fed high-fat and cholesterol diet (HFCD). The present study examined how a HFCD affects the function of NKT cells and F4/80(+) CD11b(+) subset and these hepatitis models. After the C57BL/6 mice received a HFCD, high-cholesterol diet (HCD), high-fat diet (HFD) and control diet (CD) for four weeks, the HFCD mice increased surface CD1d and intracellular TLR-9 expression by the CD11b(+) population compared to CD mice. Hepatic injury induced either by α-GalCer or CpG-ODN was more severe in HCD and HFCD mice compared to CD mice, which was in proportion to the serum TNF levels. In addition, liver cholesterol levels but not serum cholesterol levels nor liver triglyceride levels were involved in the aggravation of hepatitis. The FasL expression of NKT cells induced by both reagents was upregulated in HFCD mice. Furthermore, the liver mononuclear cells and purified F4/80(+) CD11b(+) subset from HFCD mice stimulated with either reagent in vitro produced a larger amount of TNF than did those from CD mice. Intracellular TNF production in F4/80(+) CD11b(+) cells was confirmed. The increased number of F4/80(+) CD11b(+) Kupffer cells/macrophages by HFCD and their enhanced TNF production thus play a pivotal role in TNF/NKT cell/FasL dependent hepatic injury.
Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Hiroyuki
H
Nakashima
Yoshiko
Y
Ogawa
Satoshi
S
Shono
Manabu
M
Kinoshita
Masahiro
M
Nakashima
Atsushi
A
Sato
Masami
M
Ikarashi
Shuhji
S
Seki
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002784:Cholesterol / Q000009:adverse effects*; D059305:Diet, High-Fat; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005699:Galactosylceramides / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006937:Hypercholesterolemia / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000097382:CD68 Molecule
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D002784:Cholesterol; D053222:Fas Ligand Protein; D005699:Galactosylceramides; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C408982:CPG-oligonucleotide; C505658:Fasl protein, mouse; C495370:Tlr9 protein, mouse; C493154:alpha-galactosylceramide; C036763:monocyte-macrophage differentiation antigen