Modulation of miR-155 and miR-125b Levels following Lipopolysaccharide/TNF-α Stimulation and Their Possible Roles in Regulating the Response to Endotoxin Shock

Abstract

We report here that miR-155 and miR-125b play a role in innate immune response. LPS stimulation of mouse Raw 264.7 macrophages resulted in the up-regulation of miR-155 and down-regulation of miR-125b levels. The same changes also occurred when C57BL/6 mice were i.p. injected with LPS. Furthermore, the levels of miR-155 and miR-125b in Raw 264.7 cells displayed oscillatory changes in response to TNF-α. These changes were impaired by pretreating the cells with the proteasome inhibitor MG-132, suggesting that these two microRNAs (miRNAs) may be at least transiently under the direct control of NF-κB transcriptional activity. We show that miR-155 most probably directly targets transcript coding for several proteins involved in LPS signaling such as the Fas-associated death domain protein (FADD), IκB kinase ε (IKKε), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF-α translation. In contrast, miR-125b targets the 3′-untranslated region of TNF-α transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF-α production. Finally, Eμ-miR-155 transgenic mice produced higher levels of TNF-α when exposed to LPS and were hypersensitive to LPS/d-galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF-α-dependent regulation of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets for drug design.

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

“…The downregulation of miR-125b in the U2932 LMP1 expressors thus might explain how LMP1 activates ERK1/2 and AKT pathway. The TNF-a expression increase by LMP1 (Lay et al, 2003) is consistent with the downregulation of miR-125b, observed here, as this miR targets 3 0 -UTR of TNF-a (Tili et al, 2007).…”

Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis

“…Neither MMP-3 nor MMP-1 has been predicted (by miRGen analysis) to be a direct target of miR-155. However, a recent study by Tili et al raised the possibility of an indirect action of miR-155 on the control of expression of MMP-3 and MMP-1 (42). That study demonstrated that miR-155 most probably targets proteins involved in LPS signaling, such as the Fas-associated death domain, I⌲B kinase ⑀, and the TNF receptor superfamily-interacting serinethreonine kinase 1.…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…Tnf mRNA can be directly targeted by miR-125b. 67 Moreover, miR-125b is one of the miRNAs decreased after TLR ligand treatment, thus ensuring that TNF mRNA is stabilized. Recently, miR-365 and miR-142-3p were demonstrated to target Il6 mRNA, reducing the endotoxin-induced mortality.…”

“…For the most part, primary miRNA transcription is dependent on the NF-kB transcription factor. 64,65 Additionally, TLR signals can negatively regulate miRNAs, including miR125b, let-7i and miR-98, [66][67][68] in certain cell types. Little is known about how TLR signals decrease miRNA expression, which most likely occurs through transcriptional repression or post-transcriptional destabilization of miRNA.…”