Lethal effect and apoptotic DNA fragmentation in response of D-GalN-treated mice to bacterial LPS can be suppressed by pre-exposure to minute amount of bacterial LPS: Dual role of TNF receptor 1

AIM: To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect. METHODS: Experimental groups of mice were pretreated with non-lethal amount of LPS (0.05 μg). Both control and experimental groups simultaneously were challenged with LPS plus D-GaIN for 6-7 h. The evaluations of both DNA fragmentations from the livers and the protection efficacy against lethality to mice through induction of tolerance to LPS were conducted. RESULTS: In the naive mice challenge with LPS plus D-GaIN resulted in complete death in 24 h, whereas a characteristic apoptotic DNA fragmentation was exclusively seen in the livers of mice receiving LPS in combination with D-GaIN. The mortality in the affected mice was closely correlated to the onset of DNA fragmentation. By contrast, in the mice pre-exposed to LPS, both lethal effect and apoptotic DNA fragmentation were suppressed when challenged with LPS/D-GalN. In addition to LPS, the induction of mouse tolerance to TNF also enabled mice to cross-react against death and apoptotic DNA fragmentation when challenged with TNF and/or LPS in the presence of D-GaIN. Moreover, this protection effect by LPS could last up to 24 h. TNFR1 rather than TNFR2 played a dual role in signaling pathway of either induction of tolerance to LPS for the protection of mice from mortality or inducing morbidity leading to the death of mice. CONCLUSION: The mortality of D-GalN-treated mice in response to LPS was exceedingly correlated to the onset of apoptosis in the liver, which can be effectively suppressed by brief exposure of mice to a minute amount of LPS. The induced tolerance status was mediated not only by LPS but also by TNF. The developed tolerance to either LPS or TNF can be reciprocally cross-reacted between LPS and TNF challenges, whereas the signaling of induction of tolerance and promotion of apoptosis was through TNFR1, rather than TNFR2.

MicroRNA in TLR signaling and endotoxin tolerance

Toll-like receptors(TLRs)in innate immune cells are the prime cellular sensors for microbial components.TLR activation leads to the production of proinflammatory mediators and thus TLR signaling must be properly regulated by various mechanisms to maintain homeostasis.TLR4-ligand lipopolysaccharide(LPS)-induced tolerance or cross-tolerance is one such mechanism,and it plays an important role in innate immunity.Tolerance is established and sustained by the activity of the microRNA miR-146a,which is known to target key elements of the myeloid differentiation factor 88(MyD88)signaling pathway,including IL-1 receptor-associated kinase(IRAK1),IRAK2 and tumor-necrosis factor(TNF)receptor-associated factor 6(TRAF6).In this review,we comprehensively examine the TLR signaling involved in innate immunity,with special focus on LPS-induced tolerance.The function of TLR ligand-induced microRNAs,including miR-146a,miR-155 and miR-132,in regulating inflammatory mediators,and their impact on the immune system and human diseases,are discussed.Modulation of these microRNAs may affect TLR pathway activation and help to develop therapeutics against inflammatory diseases.