The protective role of host Toll-like receptor-4 in acute graft-versus-host disease.
BACKGROUND
Mutations in Toll-like receptor (TLR)-4 have been associated with the hyporesponsiveness of macrophages to lipopolysaccharide, possibly reducing the risk of acute graft-versus-host disease (GVHD). However, TLR-4 mutations may also increase the risk of intestinal damage and microbial infection, thereby accelerating acute GVHD.


METHODS
In this study, we investigated the role of TLR-4 in triggering acute GVHD using C3H/HeJ mice with disrupted TLR-4 and C3H/HeN mice with intact TLR-4 as recipients in an acute GVHD model.


RESULTS
TLR-4 expression was significantly increased in the intestines and livers from acute GVHD mice. TLR-4-mutant C3H/HeJ hosts that received C57BL/6 (B6) donor cells developed significantly more severe GVHD than TLR-4-intact C3H/HeN hosts receiving B6 donor cells. Antibiotic treatment prolonged the survival of C3H/HeN-host GVHD mice but reduced the survival of C3H/HeJ-host GVHD mice. C3H/HeJ-host GVHD mice showed increased lipopolysaccharide levels in the blood, donor cell and CD68+ cell infiltration, tumor necrosis factor-α mRNA expression, and more apoptotic cells in the intestine compared with C3H/HeN host GVHD mice. In contrast, intestinal cyclooxygenase-2, prostaglandin E2, and hepatocyte growth factor expression in C3H/HeJ-host GVHD mice were significantly decreased compared with C3H/HeN-host GVHD mice.


CONCLUSIONS
Our results indicated that host TLR-4 is crucial for the induction of tissue protective factors and for protection against intestinal cell apoptosis during acute GVHD.
Imado
Takehito
T
Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Iwasaki
Tsuyoshi
T
Kitano
Sachie
S
Satake
Atsushi
A
Kuroiwa
Takanori
T
Tsunemi
Sachi
S
Sano
Hajime
H
D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D007113:Immunity, Innate / Q000235:genetics; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000097:blood; D008099:Liver / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015232:Dinoprostone; D017228:Hepatocyte Growth Factor; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C553307:HGF protein, mouse; C493487:Tlr4 protein, mouse; C077623:Ptgs2 protein, mouse