MafB, a target of microRNA-155, regulates dendritic cell maturation

Lu Yang; Rui Li; Shaoxun Xiang; Weihua Xiao

doi:10.1515/biol-2016-0006

Artikel Open Access

MafB, a target of microRNA-155, regulates dendritic cell maturation

Lu Yang , Rui Li , Shaoxun Xiang und Weihua Xiao

Veröffentlicht/Copyright: 29. April 2016

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Aus der Zeitschrift Open Life Sciences Band 11 Heft 1

Abstract

MafB is a member of bZip transcription factors that share similar basic region/leucine zipper DNA binding motifs and N-terminal activation domains. It is well known that MafB is highly expressed in macrophages and promotes differentiation of myeloid progenitors into macrophage. However, little is known about its function in dendritic cells. Here, we report that MafB, as a target of miR-155, which had been reported to be required for dendritic cell maturation and function, regulated dendritic cell maturation. MafB and miR-155were reversely correlated during DC maturation induced by LPS and forced expression of miR-155 reduced MafB expression. The luciferase reporter assay showed that MafB 3’UTR was directly targeted bymiR-155. In addition, knockdown of MafB promoted the phenotypic maturation of DC2.4 cells. Forced expression of MafB could significantly attenuate the phenotypic maturation of DC2.4 cells caused by overexpression of miR-155. Overall, our data demonstrates that MafB, inhibited by miR-155, was a negative regulator of DC maturation.

Keywords: MafB; miR-155; dendritic cell; maturation

1 Introduction

Dendritic cells (DCs) are the most potent professional APCs in the immune system [1]. Their main function is to process antigen and present it on the cell surface to T cells of the immune system [2] where they act as messengers between the innate and the adaptive immune systems. DCs are derived from hematopoietic bone marrow progenitor cells. These progenitor cells initially transform into immature DCs (iDCs), which are characterized by high endocytic activity and low T-cell activation potential. Once they have come into contact with a presentable antigen, they become activated into mature DCs (mDCs), with upregulation of surface costimulatory (e.g., CD80 and CD86) and MHC (class I and class II) molecules, enhancing the ability to activate T cells, producing numerous immunostimulatory cytokines, and migrating to secondary lymphoid organs [1]. The process from iDCs to mDCs is called “maturation”. MiR-155 is involved in a range of physiological and pathological processes such as tumor development and progression, cardiovascular diseases, immune cell differentiation and development etc. [3-5] Many studies have shown that miR-155 plays an indispensable role in DC functions, including antigen presenting [6], IL-12 production, apoptosis, surface marker expression [7], maturation [8,9], etc.

In the current study, through the analysis of mRNA expression and microRNA expression profiling in human monocyte-derived dendritic cells (Mo-DCs), we found that the expression of miR-155 was closely correlated to MafB. Bioinformatics prediction also suggested that MafB might be a target of miR-155. MafB is a basic leucine zipper (bZIP) transcription factor. Previous research showed that MafB played an important role in the differentiation of myeloid progenitor cells to macrophages or DCs [10]. A study in burn patients also showed that the increased MafB increased macrophages and led to defective DCs [11]. These studies suggest that MafB may play a part in the regulation of DC development or functions. Moreover, like c-Fos, MafB belongs to the AP-1 family, which forms heterodimer to function [12]. It has been demonstrated that MafB can form heterodimer with c-Fos [13]. As c-Fos is a target of miR-155, and regulates DC maturation [8], we suppose that MafB, maybe another target of miR-155, regulating DC maturation similar to c-Fos or collaborating with c-Fos.

In this study, using bone marrow-derived dendritic cells (BMDCs) from miR-155 gene knockout (miR-155^‐/‐) mice and mouse DC2.4 cells, we found that the expression of miR-155 and MafB was reversely correlated during DC maturation induced by LPS. A luciferase reporter assay showed that MafB was a target of miR-155. In addition, knockdown of MafB in DC2.4 cells enhanced the expression of co-receptors including CD40, CD80, CD83, CD86 and MHCII.Forced expression of MafB could significantly attenuate the phenotypic maturation of DCs caused by overexpression of miR-155. In conclusion, this study discovered a new target of miR-155, MafB, and demonstrated that miR-155 could regulate DC maturation partly through MafB.

2 Methods

2.1 Plasmid construction

The miR155 overexpression fragment (chr21:26,945,924- 26,946,718) was amplified by polymerase chain reaction (PCR) using human genomic DNA (Clontech) as a template with the primers homo-miR155-Fw: 5’-GCG GAT CCT TTA AAG AAG ATG ATA CAT ATG-3’ and homo-miR155-Rv: 5’-GGA ATT CGC CCA CAT TTC TAA CAG TTG A-3’, the fragment was cloned into pcDNA3.0 vector to generate the pcDNA3.0-miR155 construct. The MafB 3’UTR (1741 bp to 2243 bp) was amplified by PCR using human genomic DNA (Clontech) as a template with the primers homo-MafB- 3’UTR-Fw: 5’-ATC TCG AGC AGC TGC TTT GCT GCC CGG A-3’ and homo-MafB-3’UTR-Rv: 5’-ATG CGG CCG CCC AAA CAA AGA CCC TCA GCT-3’, the PCR product was cloned into pSI- CHECK2 vector to generate the pSI-CHECK2-MafB-3’UTR construct. The MafB 3’UTR mutation was achieved by site- directed PCR mutagenesis using the MafB 3’UTR plasmid as a template and the primers homo-MafB-3’UTR-Fw, homo-MafB-3’UTR-Rv, homo-MafB-3’UTR-mut-Fw: 5’-GAA AAA TAC AAA AAA TCT GCT AAT AAA ATA TTA ATC CTG CAT G-3’ and homo-MafB-3’UTR-mut-Rv: 5’-CAT GCA GGA TTA ATA TTT TAT TAG CAG ATT TTT TGT ATT TTT C-3’, also, the mutant fragment was cloned into pSI-CHECK2 vector. The PLKO.1 and PLKO.1-mus-MafB-shRNA plasmids were purchased from Sigma. The mus-MafB-shRNA sequences were CCG GGC TGA GTC TTT GTT TGG GTT TCT CGA GAA ACC CAA ACA AAG ACT CAG CTT TTT G. The luciferase reporter vector psi-CHECK2 and the packaging vectors of lenti-viral particles were kindly provided by Dr. M. Wu (University of Science and Technology of China, Hefei, China).

2.2 MiR155 mimics

MiR155 mimics were purchased from GenePharma (Shanghai, China) and used for the overexpression of miR155 in DC2.4 cells. DC2.4 cells were transfected at a final concentration of 25 nM. Negative control mimics were transfected as control.

2.3 Cell culture and transfection

HEK293 T cells were cultured in complete DMEM medium (Gibco) supplemented with 10% fetal bovine serum (Hyclone). DC2.4 cells were cultured in low glucose DMEM medium (Hyclone) supplemented with 10% fetal bovine serum (Hyclone), 25 mM HEPES (biosharp) and 50 µM β-mercaptoethanol (Sigma), treated with 1 µg/ml LPS (Sigma) for activation. All cells were cultured at 37°C with 5% CO₂. Lipofectamine 2000 (Invitrogen) was used for transfection following manufacture’s instruction.

2.4 Western blot analysis

The cells were harvested, boiled in 1x SDS loading buffer and resolved on SDS– PAGE. The GAPDH antibody (Santa Cruz) and MafB antibody (Abcam) were used as markers.

2.5 Bone marrow-derived dendritic cells (BMDCs) acquisition

Bone marrow-derived dendritic cells (BMDCs) were generated as described previously [14]. In brief, C57BL/6 mice were sacrificed by cervical dislocation, femurs were removed, and bone marrow cells were harvested by flushing the femurs with BMDC medium. 1 × 10⁷ bone marrow cells were then plated in a 10mm dish in complete RPMI 1640 medium (Hyclone) supplemented with 10% fetal bovine serum (Hyclone), 10 ng/ml mGM-CSF (PeproTech) and 10 ng/ml mIL-4 (PeproTech) at 37°C with 5% CO₂. The medium was half replaced with fresh BMDC medium every second day. BMDCs were further activated with 100 ng/ml LPS for 24 h on Day 7.

2.6 Lenti-viral infection

Lenti-viruses expressing the mouse MafB-shRNA were obtained by co-transfecting pLKO.1-MafB-shRNA (Sigma) with the packaging and envelope vectors (kindly provided by Dr. M. Wu) into HEK293T cells. Viral supernatants were harvested 36 h after transfection, filtered and used to infect DC2.4 cells. Puromycin (2.5 µg/ml, Merck) selection was conducted 24h post viral infection. The surviving cells were stable DC2.4 cells with MafB knockdown.

2.7 RNA isolation, reverse transcription and real-time PCR

Total RNA was isolated using TRIzol reagent (Ambion). 1µg of total RNA was reversely transcibed using an M-MLV kit (Invitrogen) following the manufacturer’s instructions. The primers of mRNA reverse transcription were random primers or oligo dT primers, the primers of microRNA reverse transcription were stem-loop primers, they were mus-miR155-RT: 5’-GTT GGC TCT GGT GCA GGG TCC GAG GTA TTC GCA CCA GAG CCA ACA CCC CT-3’ and homo- miR155-RT: 5’-GTT GGC TCT GGT GCA GGG TCC GAG GTA TTC GCA CCA GAG CCA ACA CCC CT-3’. The primers of U6 reverse transcription were sequence specific primers, mus/homo-U6-RT: 5’-AAC GCT TCA CGA ATT TGC GT-3’. For real-time PCR, we used SYBR Green Real time PCR Master Mix (Roche) and a series of qRT primers, homo/ mus-GAPDH-qRT-Fw: 5’-GGT GAA GGT CGG TGT GAA CG-3’, homo/mus-GAPDH-qRT-Rv: 5’-CTC GCT CCT GGA AGA TGG TG-3’, mus-MafB-qRT-Fw: 5’-CCT GCT GGC TCG GTG TCG TC-3’, mus-MafB-qRT-Rv: 5’-TGG GTG CGA ACC GAT GAG CG-3’, mus-miR155-qRT-Fw: 5’-GTG GGT TAA TGC TAA TTG TGA T-3’, mus/homo-miR155-qRT-Rv: 5’-GTG CAG GGT CCG AGG T-3’, homo/mus-U6-qRT-Fw: 5’-CTC GCT TCG GCA GCA CA-3’, homo/mus-U6-qRT-Rv: 5’-AAC GCT TCA CGA ATT TGC GT-3’, homo- MafB- qRT-Fw: 5’-GAC GCA GCT CAT TCA GCA G-3’, homo -MafB-qRT-Rv: 5’-CCG GAG TTG GCG AGT TTC T-3’, homo-miR155-qRT-Fw: 5’-GTG GGT TAA TGC TAA TCG TGA T-3’.

2.8 Luciferase reporter assay

Cellular lysates were subjected to a dual-luciferase reporter assay (Promega) according to the instructions of the manufacturer. In brief, miR155 overexpression vectors and pSI-CHECK2 plasmids were cotransfected into HEK293T cells, after 36 hours, cells were collected and used to a dual-luciferase reporter assay. The luciferase activities were detected by GloMax 96 Microplate Luminometer (Promega).

2.9 FACS assay

To detect the phenotype of DCs, cells were harvested and coated with antibodies representing typical surface marker molecules of DCs (BD Pharmingen) according to the instructions of the manufacturer, and multi-color flow cytometry analysis were performed using a FACSCalibur instrument (BD Biosciences). Fluorescein labeled IgG were used as the isotype control. Data were analyzed by FlowJo (Tree Star).

3 Results

3.1 MiR-155 and MafB were reversely correlated during LPS-induced DC maturation

MiR-155 was significantly upregulated during DC maturation [8]. To examine the relationship between MafB and miR-155, and whether MafB regulated DC maturation, we initially measured the expression level of miR-155 and MafB during the course of LPS-induced DC2.4 cell maturation. MiR-155 expression increased after 3 hours, then kept increasing until 24 hours, but decreased after 36-48 h (Figure 1A), which was similar to that in human monocyte-derived dendritic cells (Mo-DCs) [15]. In contrast, MafB mRNA level markedly decreased as early as 3 hours, and maintained a low level throughout the course (Figure 1B). The protein level of MafB correlated closely with its mRNA expression (Figure1C). To confirm the maturation, the surface marker of DC maturation was examined. DC2.4 cells treated with 100 ng/ml LPS for 24h showed a much higher expression of surface CD40, CD80, CD83, CD86 and MHCII than those cultured in the absence of LPS(Figure 1D). Moreover, the expression level of miR-155 increased >2 fold and the mRNA level of MafB decreased >5 fold when BMDCs derived from C57B6 mice treated with LPS compared to the control group (Figure 1D and 1E). The protein level of MafB also decreased similarly to its mRNA level in these cells. Maturation was verified by examining the up-regulation of the molecular marker CD40, CD80, CD83, CD86 and MHCII (Figure 1H). These results indicate that MafB might be regulated by miR-155 and participate in the regulation of DC maturation.

Figure 1

The expression level of miR-155 and MafB was reversely correlated during LPS-induced DC maturation. The RNA level of miR-155 (A) and the mRNA level of MafB (B) were assessed by quantitativereal-time PCR with the use of total RNA isolated from DC2.4 cells treated with mock or 1 µg/mlLPS for various time periods as indicated. The protein level of MafB (C) was assessed by western blot from DC2.4 cells treated with mock or 1ug/mlLPS for various time periods as indicated. (D) The expression of surfacemarker molecules by DC2.4 cells after 24 h of incubation in the absenceor presence of LPS was measured by flow cytometry. The expression of miR- 155 (E) and MafB mRNA (F) of unstimulated or 100 ng/ml LPS-stimulated BMDCs from C57B6 mice were analyzed by real-time RT-PCR. (G) The protein level of MafB of unstimulated or 100 ng/ml LPS-stimulated BMDCs from C57B6 mice were analyzed by western blot. (H) The expression of surface marker molecules by BMDCs after 24 h of incubation in the absence or presence of LPS was measured by flowcytometry.The means and SDs derived from3 independent experiments are shown.** and *** indicate p < 0.01 and p< 0.001, respectively.

3.2 MiR-155 negatively regulated the expression MafB

To further explore the regulatory function of miR-155 on MafB expression, we introduced miR-155 mimics into DC2.4 cells and confirmed miR-155 overexpression by RT-PCR (Figure 2A). The forced expression ofmiR-155 reduced MafB expression (Figure 2A,2B). The mRNA expression of MafB in BMDCs of miR-155^‐/‐ mice increased twofold compared to WT mice and the expression of miR-155 was confirmed by RT-PCR (Figure 2C). The protein level of MafB in BMDCs of miR-155^‐/‐ mice was also higher than that in WT mice (Figure 2D). These data indicate that miR-155 negatively regulated the expression of MafB.

Figure 2

MiR-155 negatively regulated the expression MafB. DC2.4 cells were transfected with 25 nM miR-155 or control mimics. 48 h later, total RNA was subjected to real-time RT-PCR analysis to detect RNA levels of miR-155 and MafB. Data are mean ± SD from three independent experiments. ** and *** indicate p < 0.01 and p < 0.001, respectively. (A) DC2.4 cells were transfected with 25 nM miR-155 or control mimics. 48 h later, the cells were subjected to western blot analysis to detect the protein level of MafB. (B) The expressionof miR-155 and MafB was analyzed by real-time RT-PCR with the use of total RNA isolated from BMDCs of WT or miR-155^‐/‐ C57B6 mice. The means and SDs derived from3 independent experiments are shown. ** and *** indicate p < 0.01 and p < 0.001, respectively. (C) The protein level of MafB was analyzed by western blot with the use of BMDCs from WTor miR-155^‐/‐ C57B6 mice.

3.3 MiR-155 directly targeted MafB 3’UTR

Bioinformatics prediction identified a miR-155-binding site conserved in many species in the 3’UTR of MafB, which strongly implied that MafB was a target of miR-155 (Figure 3A). To investigate whether MafB was regulated by miR-155 directly, a dual-luciferase reporter assay was conducted. The 3’UTR of human MafB mRNA was inserted into reporter vectors downstream of the Renilla luciferase gene. As a control we used vectors in which the seed regions of the predicted miR-155-binding site within the MafB 3’UTR were mutated (Figure 3B).

Figure 3

MiR-155 directly targeted MafB 3’UTR. (A) Schematic representation of human MafB mRNA. The sizes in nucleotides of the 5’UTR, open reading frame (ORF), and 3’UTR are indicated. The 3’UTR contains one predicted binding site (black box) for miR-155. The sequence of human miR-155 is shown aligned with its predicted target site in the 3’UTR of MafB mRNAs from the indicated species by Target Scan. The miR-155 seed region and its complementary sequences in MafB mRNAs are enclosed by boxes. (B) Schematic illustration of pSI-CHECK2 based luciferase reporter constructs used for examining the effect of miR-155 on the 3’ UTR of MafB. Sequences of the mutated (mut) 3’UTR of human MafB mRNA are indicated. Luciferase reporter constructs containing the WT or mutated 3’UTRs of human MafB mRNA, together with pcDNA3.0 or pcDNA3.0-miR-155were cotransfected into HEK293T cells. The expression of miR-155 was analyzed by real-time RT-PCR (C). Luciferase activity was measured 36 hours after transfection, normalized with respect to the activity obtained with a control reporter vector, and was expressed as relative luciferase activity (D). The means and SDs derived from 3 independent experiments are shown. ** and *** indicate p < 0.01 and p < 0.001, respectively.

Forced miR-155expression resulted in a significant reduction in the luciferase activity of the wildtype MafB 3’UTR (Figure 3D); however, it had no influence on the luciferase activity of the mutant MafB 3’UTR. The overexpression of miR-155 was confirmed by RT-PCR (Figure 3C). These results confirmed that the predicted miR-155-binding site in the 3’UTR of MafB was directly targeted by miR-155.

3.4 MafB regulated the phenotypic maturation of DCs

To investigate the role of MafB in DC maturation, we generated a stable polyclonal DC2.4 cell line in which the MafB gene was silenced through lentiviral infection and puromycin selection (designated hereafter as DC2.4/MafB- shrank) and compared its phenotypes with control cells (designatedhereafteras DC2.4/PLKO.1). Incomparisonwith DC2.4/PLKO.1 cells, DC2.4/MafB-shRNA cells exhibited a much lower MafB expression (Figure 4A), implying that the knockdown was effective. As expected, DC2.4/ MafB-shRNA cells showed higher expressions of surface CD40, CD80, CD83, CD86 and MHC class II molecules than DC2.4/PLKO.1 cells (Figure 4B, C), suggesting that reducing the level of MafB promoted maturation of DCs. Overexpression of miR-155 promoted the phenotypic maturation of DCs, however when overexpressing MafB together with miR-155, the phenotypic maturation of DCs caused by overexpression of miR-155 was significantly attenuated (Figure 4D). To confirm the overexpression, the protein level of MafB and the RNA level of miR-155 were detected separately (Figure 4E, F).

Figure 4

MafB regulated the phenotypic maturation of DCs. (A) DC2.4 cells were infected with lenti-virus PLKO.1 or PLKO.1-MafB-shRNA, then screened stable polyclonal cell line with puromycin. The knockdown effect of MafB was detected by real-time RT-PCR. Data are mean ± SD from three independent experiments. ** and *** indicate p < 0.01 and p < 0.001, respectively. (B) The expression of costimulatory molecules (CD40, CD80, CD83 and CD86) and MHCII on the surface of these cells were measured by flow cytometry after staining with appropriate Abs. (C) The relative MFI of costimulatory molecules (CD40, CD80, CD83 and CD86) and MHC II on the surface of these cells were shown. Data are mean±SD from three independent experiments. ** and *** indicate p < 0.01 and p < 0.001, respectively. RFI, Median Fluorescence Intensity. (D)DC2.4 cells were transfected with control mimics plus pcdna3.0 plasmid or miR-155 mimics plus pcdna3.0 plasmid or miR-155 plus pcdna3.0-MafB plasmid. After 24 h, the expression of costimulatory molecules (CD40, CD80, CD83 and CD86) and MHCII were measured by flow cytometry after staining with appropriate Abs. Part of these cells were subjected to western blot analysis to detect the protein level of MafB (E) or real-time RT-PCR analysis to detect RNA levels ofmiR-155 (F). Data are mean ± SD from three independent experiments. ** and *** indicate p < 0.01 and p < 0.001, respectively.

4 Discussion

Dendritic cells are the most potent professional APCs in immune system, and their maturation is the key step in the initiation of adaptive immune response. Triggered by diverse exogenous and endogenous mediators, such as TLR ligands (e.g., LPS), proinflammatory cytokines, alarmins, and CD40L, DCs undergo a complex phenotypic and functional maturation transformation process. Despite advances in studies on DC maturation, the mechanism involved is still not fully understood. Previous studies have shown that several transcription factors, such as NF-κB, AP-1, activating transcription factor-2, and CREB, may play important roles during DC maturation. They can either promote or inhibit numerous downstream genes’ transcription, and affect DC function. Here, we demonstrated that MafB was a new transcription factor that could regulate DC maturation.

Besides transcription factors, micro RNAs may also affect DC function, among which, miR-155 has been reported to be critical for DC maturation and function [8]. However, the molecular mechanism is still poorly understood. Through searching new targets, we found that transcription factor MafB could be a direct target of miR-155, and can participate in the regulation of DC maturation.

So far, the functions of MafB have been rarely reported and mainly focus on its roles in islet β cells [16- 19], macrophages [10,20-24] and multiple myeloma [25- 31]. Here we uncovered its new function in dendritic cell maturation. In this study, we found that the expression of MafB and miR-155 was reversely correlated during DC maturation induced by LPS. MafB was a new target of miR-155 and negatively regulated by miR-155. Knockdown of MafB in DC2.4 cells enhanced the expression of co-receptors including CD40, CD80, CD83, CD86 and MHCII. Forced expression of MafB could significantly attenuate the phenotypic maturation of DCs caused by overexpression of miR-155, which meant that miR-155 could regulate DC maturation partly through MafB.

However, the mechanism by which MafB regulates DC maturation is still unknown. Further downstream gene analysis may indicate how it affects DC function. On the other hand, it has been reported that MafB can form a heterodimer with c-Fos [32], which is another target of miR-155 and is involved in DC maturation [8], suggesting that the interaction of these two transcription factors may be important in suppressing DC maturation, and miR-155 can disrupt this by directly targeting their 3’UTR and promote DC functional maturation.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LY performed most of the experiments. RL participated in the BMDCs acquisition experiments. LY, XSX and WHX designed the experiments and wrote the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This work was supported by in part by funds from the National Basic Research Program of China (Grant No. 2013CB944903 and 2012CB825806), the National Natural Science Foundation (Grant No. 81071683, 91029710 and 81272327).

We would like to thank Dr. M. Wu in University of Science and Technology of China for the gift of the plasmid pSI-CHECK2 and the packaging vectors of lentiviral particles.

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Received: 2015-12-16

Accepted: 2016-3-25

Published Online: 2016-4-29

Published in Print: 2016-1-1

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