Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.
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.
Tili
Esmerina
E
Ohio State University, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Columbus, OH 43210, USA.
Michaille
Jean-Jacques
JJ
Cimino
Amelia
A
Costinean
Stefan
S
Dumitru
Calin Dan
CD
Adair
Brett
B
Fabbri
Muller
M
Alder
Hannes
H
Liu
Chang Gong
CG
Calin
George Adrian
GA
Croce
Carlo Maria
CM
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation
D008070:Lipopolysaccharides; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha