ABSTRACT
Toll-like receptor 3 (TLR3) is a member of the TLR family, mediating the transcriptional induction of type I interferons (IFNs), proinflammatory cytokines, and chemokines, thereby collectively establishing an antiviral host response. Studies have shown that unlike other TLR family members, TLR3 is the only RNA sensor that is utterly dependent on the Toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF). However, the details of how the TLR3-TRIF signaling pathway works in an antiviral response and how it is regulated are unclear. In this review, we focus on recent advances in understanding the antiviral mechanism of the TRIF pathway and describe the essential characteristics of TLR3 and its antiviral effects. Advancing our understanding of TLR3 may contribute to disease diagnosis and could foster the development of novel treatments for viral diseases.
ABSTRACT
Objective To investigate the effect of different antibodies on Toll-like Receptor 4-High Mobility Group Box 1 and its downstream signal transductions in distant organ injuries caused by intestinal ischemia/reperfusion in mice.Methods A total of 40 mice (C57BL/6,SPF level) were by random number table method assigned into five groups:sham,control,anti-HMGB1,anti-Myeloid differentitation gene,and antiTIR domain containing adaptor inducing IFN-β (n=8).In the control,anti-HMGB1,anti-MyD88,and antiTRIF groups,the IgG,HMGB1,MyD88,and TRIF antibodies were injected,respectively,via the tail vein 30 minutes before ischemia (1 mg/kg body weight,0.025％).After anesthesia and abdomen incision,all mice,except the sham group,underwent intestinal ischemia by clamping the superior mesenteric artery for 60 minutes followed by 60 minutes of reperfusion.Sham group underwent the same surgical procedures except for clamping the artery.Serum nuclear factor-κB p65,Interleukin-6 and Tumor Necrosis Factor-α were measured.Morphological changes in the lung and intestine were evaluated.mRNA and protein expressions of HMGB1 and NF-κB in lung and intestinal tissues were assayed.Results Compared with the control group [(228.53± 24.85),(104.91±31.18),and (70.81±46.97) ng/L],HMGB1 [(145.00±33.63),(62.28±6.73),and (52.76± 5.71) ng/L],MyD88 [(191.12± 13.22),(85.90± 17.37),and (63.19 ± 5.47) ng/L],and TRIF [(183.73±10.81),(78.14±7.38),and (59.70±4.63) ng/L] significantly decreased the serum level of NF-κB (P=0.000,0.005,0.001),IL-6 (P=0.000,0.004,0.000) and TNF-α (P=0.000,0.024,0.002) after ischemia reperfusion.Tissue injuries in the lung and intestine were also alleviated by HMGB1,MyD88,and TRIF.The anti-HMGB1,anti-MyD88,and anti-TRIF groups displayed significant elevations of HMGB1 mRNA [lung (1.89±0.18),(2.35±0.31),and (2.29±0.28),ileum (4.93±0.55),(5.96± 0.73),and (5.76±0.51)],NF-κB mRNA [lung (1.42±0.23),(1.77±0.18) and (1.70±0.13),ileum (2.23±0.55),(3.11±0.38) and (2.99±0.24)] and NF-κB protein expressions in lung and ileum tissues compared to the sham group [lung HMGB1 mRNA (1.04±0.19) (P=0.000,0.000,0.000),NF-κBmRNA (1.03±0.21) (P=0.004,0.000,0.000),ileum HMGB1 mRNA (1.14±0.54) (P=0.000,0.000,0.000),NF-κB mRNA (1.03±0.23) (P=0.000,0.000,0.000)].However,incornparison with the control group [lung HMGB1 mRNA (2.67±0.23) (P=0.000,0.035,0.016),NF-κB mRNA (2.04±0.29) (P=0.000,0.039,0.012),ileum HMGB1 mRNA (6.70±0.66) (P=0.001,0.038,0.015),NF-κBmRNA (3.71±0.53) (P=0.000,0.018,0.006)],the other three groups showed a significant down-regulation,with the most remarkable decrement in the anti-HMGB1 group.Application of anti-HMGB1,anti-MyD88,and anti-TRIF could drastically attenuate the tissue injuries in ischemia reperfusion.anti-HMGB1 exhibited the most significant effect.Conclusions HMGB1 and its downstream signals play an important role in intestinal ischemia reperfusion injuries in mice.Of two downstream signals,the TRIF-dependent pathway exerts a more important effect than that of the MyD88-dependent pathway.
ABSTRACT
Objective To research the toxicity of ethanol extracts from Poylgonum multiflorum Thunb (PMT) induced by endotoxin of Gram-negative bacteria lipopolysaccharide (LPS) in rat liver, and then investigate the hepatotoxicity mechanisms of PMT on immune inflammatory signal pathway Toll-Like receptor 4 (TLR4) -interferon regulated factor3 (IRF-3). Methods SD rats were randomly assigned into normal control, LPS (4 mg/kg), acetaminophen APAP (625 mg/kg), PMT 6 g/kg (PMT- L), PMT 12 g/kg (PMT-H), LPS+APAP and LPS+PMT-L/-H groups. The 4 groups later were injected LPS 4 mg/kg by caudal vein, after 2 h, the corresponding drugs were administered once a day for 7 consecutive days, respectively. The changes of weight of rats were observed every day. The tissue morphology of liver tissue of rats on 2 h, 14 h, 5 d, 8 d after administration were detected by hematoxylin-eosin staining respectively. Real time quantitative PCR (RT-qPCR) method and Western blotting were used to detect the expression of TLR4, TRIF and IRF3 in the TLR4 signaling pathway in liver cells. Results Two hours after the rat tail vein injection of LPS, the liver tiny granulomas of rats could be observed in LPS-induced groups, and then, the liver injury of rats in LPS group was gradually recovered. Eight Days after LPS induction, the liver tissue structure of rats in LPS group was clear and complete, but in LPS + APAP group and LPS + PMT 6 or 12 g/kg groups, the focal necrosis of hepatocytes, with inflammatory cell infiltration could be observed. The results of RT-qPCR and Western blotting showed that in oral administration of PMT groups, the expression of TLR4, TRIF and IRF-3 mRNA and protein in the liver cells had no significant change compared with the normal control group. But in 4 groups induced with LPS, the expression of TLR4, TRIF and IRF- 3 mRNA and protein in the liver cells were significantly higher than that of the normal control group and LPS group (P<0.05). Conclusion PMT can cause liver damage induced by LPS, the hepatotoxicity is related to the positive regulation of TLR4/IRF-3 signaling pathways, which is not related to the dosage of PMT. The results show that activating TLR4/IRF3 signaling pathway is one of the mechanisms of liver injury of PMT in rats induced by LPS.