Abstract
Toll-like receptors (TLRs) play a critical role in the initiation of immune responses against invading pathogens. MicroRNAs have been shown to be important regulators of TLR signaling. In this study, we have found that the stimulation of multiple TLRs rapidly reduced the levels of microRNA-92a (miRNA-92a) and some other members of the miRNA-92a family in macrophages. miR-92a mimics significantly decreased, whereas miR-92a knockdown increased, the activation of the JNK/c-Jun pathway and the production of inflammatory cytokines in macrophages when stimulated with ligands for TLR4. Furthermore, mitogen-activated protein kinase kinase 4 (MKK4), a kinase that activates JNK/stress-activated protein kinase, was found to be directly targeted by miR-92a. Similar to the effects of the miR-92a mimics, knockdown of MKK4 inhibited the activation of JNK/c-Jun signaling and the production of TNF-α and IL-6. In conclusion, we have demonstrated that TLR-mediated miR-92a reduction feedback enhances TLR-triggered production of inflammatory cytokines in macrophages, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.
Highlights
We have found that the stimulation of multiple Toll-like receptors (TLRs) rapidly reduced the levels of microRNA-92a and some other members of the miRNA-92a family in macrophages. miR-92a mimics significantly decreased, whereas miR-92a knockdown increased, the activation of the Jun NH2-terminal kinases (JNK)/c-Jun pathway and the production of inflammatory cytokines in macrophages when stimulated with ligands for TLR4
Several microRNAs have been shown to target the 3Ј-untranslated regions of mRNAs encoding components of the TLR signaling system [26, 50]. miR-146 was shown to be induced by LPS, TNF-␣, and IL-1, and in turn, miR-146a acted as a negative regulator for fine-tuning the immune response mainly through targeting tumor necrosis factor receptor-associated factor (TRAF) 6 and interleukin-1 receptor-associated kinase (IRAK) 1 [50]
Inhibition of miR-155 in dendritic cells resulted in the up-regulated expression of components of the p38 mitogen-activated protein kinase (MAPK) pathway by targeting TAK1-binding protein 2 (TAB2) [24]
Summary
Results: miR-92a decreases rapidly in macrophages once stimulated with TLR ligands, and miR-92a controls inflammatory response by targeting MKK4/JNK/c-Jun pathway. MiR-92a mimics significantly decreased, whereas miR-92a knockdown increased, the activation of the JNK/c-Jun pathway and the production of inflammatory cytokines in macrophages when stimulated with ligands for TLR4.
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