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

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- (cid:1) . 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- (cid:2) B 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), I (cid:2) B kinase (cid:3) (IKK (cid:3) ), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF- (cid:1) translation. In contrast, miR-125b targets the 3 (cid:1) -untrans-lated region of TNF- (cid:1) transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF- (cid:1) production. Finally, E (cid:4) -miR-155 transgenic mice produced higher levels of TNF- (cid:1) when exposed to LPS and were hypersensitive to LPS/ D -galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF- (cid:1) -dependent of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets drug (cid:1) B activity is required for the rapid changes in miR-125b and miR-155 levels following TNF- (cid:2) stimulation