Dendritic cells of the immune system have a key role in regulating immune responses. They detect foreign stimuli from microbes such as lipopolysaccharides (LPS) through Toll-like receptor 4 and activate signaling pathways that lead to production of interferon and cytokines and to consequent activation of T cells. But unrestrained signaling in this way can lead to excessive inflammation or autoimmunity. Ceppi et al. report that a microRNA (miRNA)–mediated negative feedback loop helps modulate inflammatory responses of human dendritic cells. The authors used a microarray-based screen to detect miRNAs that increased in abundance in human monocyte-derived dendritic cells that had been exposed to LPS. They confirmed increased expression of two miRNAs, miR-155 and miR146a. The authors used expression of an oligonucelotide containing modified nucleic acid analogs to deplete miR-155 in stimulated dendritic cells and then used microarray analysis to detect alterations in mRNA expression. Sorting of the mRNAs that showed altered expression in Ingenuity Pathway analysis software indicated increased expression of components of signaling pathways initiated by the related Toll-like receptors and interleukin-1 receptor. To search for direct targets, Ceppi et al. screened the mRNAs that increased in abundance when miR-155 was inhibited for sequences predicted to be direct targets of the miRNA with TargetScan software. This implicated TAB2 (TAK1 binding protein 2), an adaptor protein that has multiple functions in IL-1 signaling. Expression of reporter constructs in 293T cells indicated that TAB-2 may be a direct target of miR-155. Furthermore, amounts of endogenous TAB2 mRNA and protein were increased in dendritic cells activated with LPS. The authors point out that, as might be expected of such a system with both important beneficial and potentially harmful actions, regulation of IL-β is highly redundant, occurring at the levels of gene expression, protein synthesis, protein processing, and protein secretion.
M. Ceppi, P. M. Pereira, I. Dunand-Sauthier, E. Barras, W. Reith, M. A. Santos, P. Pierre, MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 106, 2735–2740 (2009). [Abstract] [Full Text]