MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

Abstract

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.

miR-101a and miR-30b contribute to inflammatory cytokine-mediated β-cell dysfunction

“…17,18 Previous studies demonstrated that expression of miR-101a is modulated by the PI3K/Akt signaling pathway, which is activated in response to IL-1β. 19,20 Wei et al 21 have demonstrated that miR-30b is positively regulated by NF-κB. Therefore, we believe that IL-1β alone is capable of inducing alterations in miR-101a and miR-30b expression, and that IL-1β-mediated signaling pathways participate in the induction of miR-101a and miR-30b in β-cells, though the latter hypothesis requires further investigation.…”

Molecular Mechanism Responsible for the Priming of Macrophage Activation

“…Instead, a slight yet significant reduction in IRAK-M occurs after 2 h of super low dose LPS treatment. Other negative regulatory pathways induced by high dose LPS include the PI3K pathway that contributes to the suppression of IRAK-1/ TNF receptor-associated factor 6 (22), the induction of negative regulators, including IRAK-M (25,31), and the induction of negative transcriptional suppressors of inflammatory genes such as RelB and cAMP response element-binding (32,33). Thus, we tested the effects of super low dose LPS on the activation status of PI3K pathway.…”

“…For example, IB␣ suppresses p65/RelA by secluding it in the cytoplasm; MAPK phosphatase 1 suppresses the activities of MAP kinases (20); IRAK-M suppresses interleukin receptor-associated kinase 1 (IRAK-1) (21); and RelB blocks the transcription of proinflammatory mediators by assembling a suppressive complex on their promoters (19). In addition, LPS is known to activate the phosphoinositide 3-kinase (PI3K) pathway, which dampens the expression of proinflammatory mediators through inducing negative regulators, including MAPK phosphatase 1, IRAK-M, and suppressing IRAK-1 (22)(23)(24)(25)(26). As a consequence, LPS (Ͼ1 ng/ml) causes a robust yet transient expression of proinflammatory media-tors, followed by a refractory tolerant state.…”

MicroRNAs in Invasion and Metastasis in Lung Cancer

“…Raf kinase inhibitory protein suppresses a cascade of metastasis signalling involving LIN28 and let-7 [65]. Zhu and his colleagues found that miR-101 targets MAPK phosphatase 1 to regulate the activation of MAPKs in macrophages [66]. MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer [67].…”