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.

MicroRNAs are short non-coding RNAs that posttranscriptionally modulate the expression of multiple target genes and are thus implicated in a wide array of cellular and developmental processes. miR-155 is processed from BIC, a non-coding transcript highly expressed in both activated B and T cells and in monocytes/macrophages. miR-155 levels change dynamically during both hematopoietic lineage differentiation and the course of the immune response. Different mouse models developed recently indicate that miR-155 plays a critical role during hematopoiesis and regulates lymphocyte homeostasis and tolerance. A moderate increase of miR-155 levels is observed in many types of malignancies of B cell or myeloid origin, and transgenic over-expression of miR-155 in mice results in cancer. While the high levels of miR-155 reached transiently during the course of the immune response remain unharmful for the organism, the reason why a moderate up-regulation of miR-155 can lead to cancer remains obscure. As prolonged exposure to inflammation can lead to cancer, the permanent up-regulation of miR-155 might be a link between the two. Therefore, designing miR-155 based therapies will require a better understanding of the molecular basis of its action as well as of how miR-155 levels are regulated in a cell-specific manner.