MicroRNA-101 targets MAPK phosphatase-1 to regulate the activation of MAPKs in macrophages.
MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.
Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Qing-Yuan
QY
Zhu
Qin
Q
Liu
Jian-Xia
JX
Chen
Ke
K
Lan
Bao-Xue
BX
Ge
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D035683:MicroRNAs; D051193:Toll-Like Receptors; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse