Silencing of c-Fos expression by microRNA-155 is critical for dendritic cell maturation and function

Abstract

IntroductionMicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that regulate mRNAs by binding to their 3Ј untranslated (3ЈUTR) regions. 1,2 More than 9000 miRNAs have been identified in more than 100 species. Most miRNA genes are transcribed by RNA polymerase II into primary miRNA transcripts that are processed in the nucleus by a complex containing the RNase III endonuclease Drosha. 1 The resulting precursor miRNAs are transported to the cytoplasm, where the mature miRNAs are excised by a complex containing the endonuclease Dicer. 1 Mature miRNAs are incorporated into the RNA-induced silencing complex, which binds to the 3ЈUTRs of target mRNAs, inducing their degradation and/or repressing their translation. Posttranscriptional regulation of gene expression by miRNAs is critical for a wide range of physiologic and pathologic processes, including cell proliferation, apoptosis, differentiation, morphogenesis, development, and oncogenesis. [1][2][3][4] Several miRNAs play pivotal roles in the immune system. 5-7 MicroRNA-155 (miR155) has emerged as a particularly prominent player in innate and adaptive immune responses. 5,7 miR155 is derived from an exon of the B-cell integration cluster (BIC) gene, which was identified as a common integration site of avian leucosis virus in chicken B-cell lymphomas. 8,9 BIC is a non-protein-coding gene for which the only known function is the production of miR155. Subsequent studies revealed that miR155 expression is deregulated in diverse cancers. 10,11 The molecular mechanisms underlying the oncogenic role of miR155 remain unclear. miR155 expression is induced during the activation of T cells, B cells, monocytes, macrophages, and dendritic cells (DCs), suggesting that it plays multiple roles in the immune system. 5 In agreement with this, the immune system of miR155-deficient mice is compromised by defects in several cell types. 12,13 Activated T cells from miR155 Ϫ/Ϫ mice exhibit a bias toward Th2 differentiation and express elevated levels of IL4, IL5, and IL10. This was attributed to the fact that miR155 targets the mRNA coding for c-Maf, a transcription factor implicated in IL-4 expression and Th2 differentiation. 12 The B-cell compartment in miR155 Ϫ/Ϫ mice exhibits defects in germinal center development and in the generation of efficient antibody responses. miR155 is critical for affinity maturation because the generation of plasma cells produces high-affinity isotype-switched antibodies and the development of memory B cells. [12][13][14] The B-cell defects in miR155 Ϫ/Ϫ mice result at least in part from miR155 repressing the expression of the transcription factor PU.1 14 and activation-induced cytidine deaminase. 15,16 Lastly, bone marrow-derived DCs (BM-DCs) from miR155 Ϫ/Ϫ mice are impaired in their ability to activate T cells. 12 We recently reported that the induction of miR155 expression in human monocyte-derived DCs (Mo-DCs) exposed to the TLR4 ligand lipopolysaccharide (LPS) leads to modulation of the IL1 signal transduction pathway. 17 Another study foun...

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…The up-regulation was attenuated in in vitro-derived moDCs from miR-155-/-mice, leading to reduced antigen presentation and IL-2 production by T cells (Dunand-Sauthier et al, 2011). Similar to miR-155, low expression of let-7i reduced CD80 and CD86 expression by LPS-stimulated moDCs and SOCS1 acts as a target of let-7i (Zhang et al, 2011).…”

“…Transcription factor c-Fos as a target of miR-155 was negatively for moDC maturation (Dunand-Sauthier et al, 2011). Similarly for what was described for regulation of IL-6 by miR-155 (Ceppi et al, 2009;O'Connell et al, 2010;Dunand-Sauthier et al, 2011), a positive role for miR-155 in mouse moDC maturation is contrasted by a reported negative role of miR-155 for maturation of human moDC, at least based on DC-Sign expression (Martinez-Nunez et al, 2009). Maturation from monocytes into moDCs was also found to be correlated with decreased miR-211 (Lu et al, 2011a).…”

“…However, two subse-© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 quent studies showed that miR-155 could also act as a positive regulator for production of several pro-inflammatory cytokines including IL-6, IL-23, IL-12 and TNF-α by LPS-stimulated in vitro derived mouse moDCs (O'Connell et al, 2010;Dunand-Sauthier et al, 2011). The modulation of cytokine production by miR-155 is explained by miR-155 targeting negative regulators of signalling: SOCS1 and SHIP1 (O'Connell et al, 2009;Lu, 2009).…”

“…Similarly, inhibition of miR-511 and miR-99b resulted in reduced DC-SIGN levels (Tserel et al, 2011). As being a versatile miRNA, miR-155 is also positively involved in maturation of mouse moDCs (Dunand-Sauthier et al, 2011;Lu et al, 2011a). Transcription factor c-Fos as a target of miR-155 was negatively for moDC maturation (Dunand-Sauthier et al, 2011).…”

“…As being a versatile miRNA, miR-155 is also positively involved in maturation of mouse moDCs (Dunand-Sauthier et al, 2011;Lu et al, 2011a). Transcription factor c-Fos as a target of miR-155 was negatively for moDC maturation (Dunand-Sauthier et al, 2011). Similarly for what was described for regulation of IL-6 by miR-155 (Ceppi et al, 2009;O'Connell et al, 2010;Dunand-Sauthier et al, 2011), a positive role for miR-155 in mouse moDC maturation is contrasted by a reported negative role of miR-155 for maturation of human moDC, at least based on DC-Sign expression (Martinez-Nunez et al, 2009).…”