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A critical role of toll-like receptor 4 (TLR4) and its' in vivo ligands in basal radio-resistance.

Liu C, Zhang C, Mitchel RE, Cui J, Lin J, Yang Y, Liu X, Cai J - Cell Death Dis (2013)

Bottom Line: We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation.Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation.Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, People's Republic of China.

ABSTRACT
Toll-like receptor-4 (TLR4) plays a critical role in innate and acquired immunity, but its role in radio-resistance is unknown. We used TLR4 knockout (KO,(-/-)) mice and gut commensal depletion methods, to test the influence of TLR4 and its' in vivo agonist on basal radio-resistance. We found that mice deficient in TLR4 were more susceptible to IR-induced mortality and morbidity. Mortality of TLR4-deficient mice after IR was associated with a severe and persistent bone marrow cell loss. Injection of lipopolysaccharide into normal mice, which is known to activate TLR4 in vivo, induced radio-resistance. Moreover, TLR4 in vivo ligands are required for basal radio-resistance. We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation. The circulating endotoxins appear to originate from the gut, as sterilization of the gut with antibiotics lead to increased mortality from radiation. Further data indicated that Myd88, but not TRIF, may be the critical adaptor in TLR4-induced radio-resistance. Taken together, these data strongly suggest that TLR4 plays a critical role in basal radio-resistance. Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation. Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

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The radio-protective role of TLR4 agonist LPS in a TLR4 dependent manner. (a) LPS can protect TLR4+/− mice, but not TLR4−/− mice, from radiation damage. N=10, three repeats. (b) Male C57BL/10 mice, 6 weeks of age, injected with TLR4 specific in vivo KD reagents or with non-specific control in vivo KD reagents (From ABI, once a day for 2 days, N=12 in each group). Forty-eight hours later mice were treated with or without LPS at 2.5 mg/kg body weight for another 24 h, and then exposed to 7 Gy. The figure shows the survival rate of each group. *P<0.05; NS: No significant difference detected
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fig7: The radio-protective role of TLR4 agonist LPS in a TLR4 dependent manner. (a) LPS can protect TLR4+/− mice, but not TLR4−/− mice, from radiation damage. N=10, three repeats. (b) Male C57BL/10 mice, 6 weeks of age, injected with TLR4 specific in vivo KD reagents or with non-specific control in vivo KD reagents (From ABI, once a day for 2 days, N=12 in each group). Forty-eight hours later mice were treated with or without LPS at 2.5 mg/kg body weight for another 24 h, and then exposed to 7 Gy. The figure shows the survival rate of each group. *P<0.05; NS: No significant difference detected

Mentions: In vivo experiments were performed to determine whether the radio-protective role of TLR4 agonist LPS was TLR4 dependent. As shown in Figure 7a, LPS can protect TLR4+/−mice from radiation damage, but TLR4 agonist LPS displayed no radio-protective effect on the survival of TLR4−/−mice. On the contrary, LPS reduced the radio-resistance of TLR4−/−mice (Figure 7a). A similar response was seen in TLR4 in vivo KD experiments using C57BL/10 mice. As shown in Figure 7b, mice injected with the TLR4 specific in vivo KD reagents displayed less ability to be protected by LPS than mice injected with the non-specific control in vivo KD reagents. Thus, we conclude that radio-protection by TLR4 agonist LPS is TLR4 dependent.


A critical role of toll-like receptor 4 (TLR4) and its' in vivo ligands in basal radio-resistance.

Liu C, Zhang C, Mitchel RE, Cui J, Lin J, Yang Y, Liu X, Cai J - Cell Death Dis (2013)

The radio-protective role of TLR4 agonist LPS in a TLR4 dependent manner. (a) LPS can protect TLR4+/− mice, but not TLR4−/− mice, from radiation damage. N=10, three repeats. (b) Male C57BL/10 mice, 6 weeks of age, injected with TLR4 specific in vivo KD reagents or with non-specific control in vivo KD reagents (From ABI, once a day for 2 days, N=12 in each group). Forty-eight hours later mice were treated with or without LPS at 2.5 mg/kg body weight for another 24 h, and then exposed to 7 Gy. The figure shows the survival rate of each group. *P<0.05; NS: No significant difference detected
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674368&req=5

fig7: The radio-protective role of TLR4 agonist LPS in a TLR4 dependent manner. (a) LPS can protect TLR4+/− mice, but not TLR4−/− mice, from radiation damage. N=10, three repeats. (b) Male C57BL/10 mice, 6 weeks of age, injected with TLR4 specific in vivo KD reagents or with non-specific control in vivo KD reagents (From ABI, once a day for 2 days, N=12 in each group). Forty-eight hours later mice were treated with or without LPS at 2.5 mg/kg body weight for another 24 h, and then exposed to 7 Gy. The figure shows the survival rate of each group. *P<0.05; NS: No significant difference detected
Mentions: In vivo experiments were performed to determine whether the radio-protective role of TLR4 agonist LPS was TLR4 dependent. As shown in Figure 7a, LPS can protect TLR4+/−mice from radiation damage, but TLR4 agonist LPS displayed no radio-protective effect on the survival of TLR4−/−mice. On the contrary, LPS reduced the radio-resistance of TLR4−/−mice (Figure 7a). A similar response was seen in TLR4 in vivo KD experiments using C57BL/10 mice. As shown in Figure 7b, mice injected with the TLR4 specific in vivo KD reagents displayed less ability to be protected by LPS than mice injected with the non-specific control in vivo KD reagents. Thus, we conclude that radio-protection by TLR4 agonist LPS is TLR4 dependent.

Bottom Line: We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation.Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation.Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, People's Republic of China.

ABSTRACT
Toll-like receptor-4 (TLR4) plays a critical role in innate and acquired immunity, but its role in radio-resistance is unknown. We used TLR4 knockout (KO,(-/-)) mice and gut commensal depletion methods, to test the influence of TLR4 and its' in vivo agonist on basal radio-resistance. We found that mice deficient in TLR4 were more susceptible to IR-induced mortality and morbidity. Mortality of TLR4-deficient mice after IR was associated with a severe and persistent bone marrow cell loss. Injection of lipopolysaccharide into normal mice, which is known to activate TLR4 in vivo, induced radio-resistance. Moreover, TLR4 in vivo ligands are required for basal radio-resistance. We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation. The circulating endotoxins appear to originate from the gut, as sterilization of the gut with antibiotics lead to increased mortality from radiation. Further data indicated that Myd88, but not TRIF, may be the critical adaptor in TLR4-induced radio-resistance. Taken together, these data strongly suggest that TLR4 plays a critical role in basal radio-resistance. Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation. Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

Show MeSH
Related in: MedlinePlus