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Comparative Study
. 2007 Oct 15;179(8):5082-9.
doi: 10.4049/jimmunol.179.8.5082.

Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock

Esmerina Tili  1 , Jean-Jacques Michaille, Amelia Cimino, Stefan Costinean, Calin Dan Dumitru, Brett Adair, Muller Fabbri, Hannes Alder, Chang Gong Liu, George Adrian Calin, Carlo Maria Croce
Affiliations
Comparative Study

Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock

Esmerina Tili et al. J Immunol. .

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-alpha. 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-kappaB 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), IkappaB kinase epsilon (IKKepsilon), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF-alpha translation. In contrast, miR-125b targets the 3'-untranslated region of TNF-alpha transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF-alpha production. Finally, Emu-miR-155 transgenic mice produced higher levels of TNF-alpha when exposed to LPS and were hypersensitive to LPS/d-galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF-alpha-dependent regulation of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets for drug design.

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