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.
Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Takehito
T
Imado
Tsuyoshi
T
Iwasaki
Sachie
S
Kitano
Atsushi
A
Satake
Takanori
T
Kuroiwa
Sachi
S
Tsunemi
Hajime
H
Sano
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