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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.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.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.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.