Inhibitor of IκB kinase activity, BAY 11-7082, interferes with interferon regulatory factor 7 nuclear translocation and type I interferon production by plasmacytoid dendritic cells
© Miyamoto et al.; licensee BioMed Central Ltd. 2010
Received: 15 February 2010
Accepted: 14 May 2010
Published: 14 May 2010
Plasmacytoid dendritic cells (pDCs) play not only a central role in the antiviral immune response in innate host defense, but also a pathogenic role in the development of the autoimmune process by their ability to produce robust amounts of type I interferons (IFNs), through sensing nucleic acids by toll-like receptor (TLR) 7 and 9. Thus, control of dysregulated pDC activation and type I IFN production provide an alternative treatment strategy for autoimmune diseases in which type I IFNs are elevated, such as systemic lupus erythematosus (SLE). Here we focused on IκB kinase inhibitor BAY 11-7082 (BAY11) and investigated its immunomodulatory effects in targeting the IFN response on pDCs.
We isolated human blood pDCs by flow cytometry and examined the function of BAY11 on pDCs in response to TLR ligands, with regards to pDC activation, such as IFN-α production and nuclear translocation of interferon regulatory factor 7 (IRF7) in vitro. Additionally, we cultured healthy peripheral blood mononuclear cells (PBMCs) with serum from SLE patients in the presence or absence of BAY11, and then examined the inhibitory function of BAY11 on SLE serum-induced IFN-α production. We also examined its inhibitory effect in vivo using mice pretreated with BAY11 intraperitonealy, followed by intravenous injection of TLR7 ligand poly U.
Here we identified that BAY11 has the ability to inhibit nuclear translocation of IRF7 and IFN-α production in human pDCs. BAY11, although showing the ability to also interfere with tumor necrosis factor (TNF)-α production, more strongly inhibited IFN-α production than TNF-α production by pDCs, in response to TLR ligands. We also found that BAY11 inhibited both in vitro IFN-α production by human PBMCs induced by the SLE serum and the in vivo serum IFN-α level induced by injecting mice with poly U.
These findings suggest that BAY11 has the therapeutic potential to attenuate the IFN environment by regulating pDC function and provide a novel foundation for the development of an effective immunotherapeutic strategy against autoimmune disorders such as SLE.
Although only a small fraction of cells, plasmacytoid dendritic cells (pDCs) represent a major source of type I interferons (IFNs) in peripheral blood mononuclear cells (PBMCs) and lymphoid tissues in both humans and mice [1, 2], they play a central role in the innate antiviral immune response by their ability to rapidly produce robust amounts of type I IFNs upon viral infection. This function is through their selective expression of toll-like receptor (TLR)7 and TLR9, which respectively sense viral RNA and DNA within the early endosomes . Recent studies have uncovered the molecular basis underlying the specialized ability of pDCs to mount their rapid and massive IFN response. The type I IFN production requires IFN regulatory factor (IRF)7 to be phosphorylated and translocated into the nucleus through rapid interaction with MyD88 and IRF7 . pDCs are found to constitutively express high levels of IRF7 and the endogenous IRF7 facilitates a rapid type I IFN response that is independent of type I IFN receptor-mediated feedback signaling [3, 5, 6]. IRF7 is activated by forming cytoplasmic multiple signal-transducing complex with tumor necrosis factor (TNF) receptor-associated factor (TRAF)6 and interleukin (IL)-1 receptor-associated kinase (IRAK)4 through ubiquitylation and phosphorylation, and in turn interacts with TRAF3, IRAK1, osteopontin, and phosphatidylinositol-3 kinase (PI3K) [7–10]. A recent observation that pDCs barely express the translational inhibitors 4E-BP1 and 4E-BP2, which play a role in repression of Irf7 mRNA translation , could plausibly explain the constitutive expression of high levels of IRF-7 in pDCs. Thus, these unique molecular mechanisms endow pDCs with the specialized innate ability of IFN response upon viral infection.
Alternatively, a series of recent analyses have revealed that pDCs also play a pathogenic role in autoimmune diseases such as systemic lupus erythematosus (SLE) and psoriasis by their dysregulated production of type I IFNs through engagement of endosomal TLR9 by self-DNA with autoantibody [12–15]. Secretion of type I IFNs is believed to be a central molecular event that initiates and promotes the autoimmune process [12, 14]. Type I IFNs induce the differentiation of myeloid DCs from monocytes, which in turn promote the differentiation of autoreactive CD4+ T cells, CD8+ T cells, and B cells. These autoreactive effectors injure tissues, resulting in the production of nucleic acid fragment and auto anti-nuclear antibody. This in turn induces the production of immune complexes containing self-DNA or RNA. The immune complexes further activate pDCs through TLRs in a sustained fashion, amplifying the vicious spiral based on the type I IFNs. Accordingly, pDCs and type I IFNs represent specific cellular and molecular targets in therapeutic strategies against these autoimmune diseases.
BAY11-7082 (BAY11), (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, was initially identified as a compound that inhibits the NF-κB pathway and leads to the decreased expression of endothelial cell adhesion molecules  and paw swelling in a rat adjuvant arthritis model . Further studies searching for alternative therapeutic strategies against malignancies have shown that this compound is a potent inducer of apoptosis in a number of malignant cells such as in colorectal cancer  and breast cancer , as well as leukemia, myeloma cells, and lymphoma cells [20–24].
BAY11 is found to inhibit the upstream signaling process of NF-κB activation; namely it functions as an inhibitor for the action of the IκB kinase (IKK) complex, which consists of the catalytic kinase subunits IKKα and IKKβ [18, 25].
Given a recent study showing that the activation of IRF7 depends on an IKK subfamily IKKα at the downstream of the TLR7/9-MyD88 pathway in pDCs , IKKα would be a potential molecular target for the treatment of type I IFN-related autoimmune diseases. As might be inferred from the function of BAY11 as inhibitor of IKK activity, we hypothesized that this compound could have the potential to repress the IFN response in pDCs through preventing IRF7 nuclear translocation, which may lead to an alternative treatment strategy for the autoimmune diseases.
We here show a novel function of BAY11, which inhibited IFN-α production by human pDCs as well as mouse pDCs upon TLR ligand activation by inhibiting the nuclear translocation of IRF7. We also showed its inhibitory effect in vivo by the observation that treatment with BAY11 attenuates the elevated level of serum type I IFNs in mice that were injected with TLR ligands. Our current results serve as the foundation for the development of an effective immunotherapeutic strategy to repress the autoimmune disorders induced by type I IFNs.
Materials and methods
Media and reagents
RPMI-1640 supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 ng/ml streptomycin and heat-inactivated 10% fetal bovine serum (Biosource International, Camarillo, CA, USA) was used for cell cultures throughout the experiments. For human cell stimulation, we used 5 μM CpG-ODNs 2216 (Invivogen, San Diego, CA, USA), 100 μM Loxoribine (Invivogen), 1 μg/ml R848 (Invivogen), and 10 μg/ml Poly(I:C) (Invivogen). For mouse cell stimulation, we used 3 μg/ml polyuridine RNA (Poly U) (Sigma-Aldrich, St. Louis, MO, USA) in complex with lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) according to the manufactuer's protocol. BAY11-7082 (Alexis, San Diego, CA, USA) was dissolved in DMSO. DMSO was diluted in parallel to serve as a vehicle control.
Cell isolation and culture
Human peripheral blood DC subsets (myeloid DCs and pDCs) were isolated from PBMCs from healthy adult donors, as described previously [3, 27]. Written informed consent was obtained from all healthy adult donors. CD11c+/BDCA4-/lineage-/CD4+ cells (as myeloid DCs) and CD11c-/BDCA4+/lineage-/CD4+ cells (as pDCs) were sorted by FACS Aria® (BD Biosciences, San Jose, CA, USA) to reach greater than 99% purity according to restaining with anti-BDCA1 or anti-BDCA2. Mouse splenic pDCs (CD11c+B220+CD11b-) were isolated by FACS Aria® as described previously . The DC subsets or PBMCs were preincubated for 15 minutes or 1 h with BAY11 (10-9 to 10-5 M) or vehicle. Poly(I:C), CpG, R848, Loxoribine, or poly U+lipofectamine was then added into this culture in flat-bottomed 96-well plates at 5 × 104 cells (2 × 105 cells for PBMCs) in the final 200 ml of medium per well for 24 h.
Lupus PBMCs and serum, and preparation of necrotic cell supernatants
PBMCs and sera were obtained from three active SLE patients with low complements prior to steroid therapy and who satisfied five criteria in the American College of Rheumatology (ACR) classification for SLE . Written informed consent was obtained for all SLE patients. All patients had anti-double-stranded DNA antibody. Necrotic cell supernatants were prepared from KM-H2 (human Hodgkin's Reed-Sternberg line), which was grown in RPMI with 20% of fetal bovine serum, and necrosis was induced by the freeze-thaw method. Briefly, freeze-thawing was performed in four cycles of both 10 minutes freezing at -80°C and thawing at 37°C. Lupus-PBMCs were stimulated with CpG-2216 with autologous 20% serum in flat-bottomed 48-well plates at 106 cells in 500 μl of medium per well. Alternatively, healthy PBMCs were stimulated with 20% lupus serum with or without 20% necrotic cell supernatant in flat-bottomed 96-well plates at 2 × 105 cells in 200 μl of medium per well. This study was approved by the Institutional Review Board of Kansai Medical University and the research was in compliance with the Helsinki declaration.
In vivoassessment of cytokine productions
C57BL/6 mice (purchased from CLEA Japan, Meguro, Tokyo, Japan) were pretreated with BAY11 (10 mg/kg or 5 mg/kg bodyweight) or vehicle as control for 1 h intraperitonealy, followed by intravenous injection of poly U (50 μg/head) + in vivo-jetPEI (Polyplus-transfection, lllkirch, France) (according to the manufacturer's protocol). We analyzed the serum IFN-α levels at several time points (one, three, and six hours). All mice were maintained until used in the animal facilities under specific pathogen-free conditions. All animal researches were reviewed and approved by the Animal Ethical Committee of RIKEN Research Center.
Analyses of cells
Human pDCs were stained with FITC-labeled CD86 (BD Biosciences) and then analyzed by FACScalibur® (BD Biosciences). The production of cytokines in the culture supernatants after 24 hours was determined by ELISA (ELISA kits for human and mouse TNF-a and IL-12 p40 were purchased from R&D systems, (Minneapolis, MN, USA). ELISA Kits for human and mouse IFN-a were purchased from PBL Biomedical Laboratories (Piscataway, NJ, USA).
Intracellular cytokine staining in human pDCs was performed after eight hours of culture with different stimuli. Brefeldin A (10 μg/ml; Sigma-Aldrich, St. Louis, MO, USA) was added during the last two hours. After stimulation, cells were fixed and permeabilized using the FIX and PERM kit (Invitrogen, Carlsbad, CA, USA) and then stained with FITC-labeled anti-IFN-α2 mAb (Chromaprobe, Maryland Heights, MO, USA) phycoerythrin (PE)-labeled anti-TNF-α mAb (PBL Biomedical Laboratories), and allophycocyanin (APC)-labeled anti-BDCA4 mAb (Miltenyi Biotec, Bergisch Gladbach, Germany). Dead cells were excluded on the basis of side- and forward-scatter characteristics. In the viability assay, cells were washed with phosphate-buffered saline(PBS) containing 2 mM EDTA, and viable cells were counted in triplicate with trypan-blue exclusion of the dead cells. Viable cells were also evaluated using Propidium Iodide staining (Calbiochem, San Diego, CA, USA).
Detection of p-NF-κB p65 expression
Human pDCs were stimulated with CpG-2216 or loxoribine at 90 minutes, and the cells were immediately fixed and stained with Alexa Fluor-488 anti-p-NF-κB p65 (pS529; BD Biosciences) according to BD Phosflow's instructions, and then analyzed by FACS calibur.
Cells were seeded on glass slides by cytospin and mounted, and were then fixed with 2% paraformaldehyde and permeabilized with 100% ice-cold methanol for 10 minutes at -20°C. Samples were labeled with rabbit polyclonal anti-human IRF-7 (H-246, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and 4',6'-diamidino-2-phenylindole (DAPI). Anti-rabbit IgG-Cy5 (Invitrogen, Carlsbad, CA, USA) was used as secondary antibody. Images were acquired using a confocal microscope (LSM 510 META; Carl Zeiss, Inc. (Jena, Germany)).
BAY11 inhibits IFN-α production from human PBMCs
BAY11 directly inhibits IFN-α production from human pDCs
We further investigated the effect of BAY11 on the pDC maturation. Up to 3 × 10-7 M of BAY11 did not influence the CD86 expression on pDCs in response to CpG or loxoribine (Figure 2C).
BAY11 is incapable of interfering with poly IC-induced IFN-α production from myeloid DCs
BAY11 inhibits nuclear translocation of IRF7 in pDCs
Unlike type I IFN production, inflammatory cytokine and chemokine production have been shown to be mostly through NF-κB activation . Because BAY11 was initially identified as a potent inhibitor of NF-κB pathway, we confirmed its function in regard to NF-κB activation in pDCs. Analysis with flow cytometry (Figure 5C) showed that although 10-9 M and 10-8 M of BAY11 only slightly decreased the intensity of TLR-induced NF-κB phosphorylation, 10-7 M of BAY11 strongly interfered with the NF-κB phosphorylation in accord with TNF-α production (Figure 3A).
BAY11 inhibits both IFN-α production by lupus-PBMCs and lupus serum-induced IFN-α production
BAY11 inhibits inducible IFN-α production in vivo
The present study shows that IKK-neutralizing compound BAY11 affects IFN-α production mainly through its action on pDCs. IFN-α production is differentially regulated from other inflammatory cytokine production by the specific intracellular signaling under TLR activation . A key molecular switch responsible for IFN-α synthesis in pDCs is the nuclear translocation of IRF7 . We here found that BAY11 inhibits the nuclear translocation of IRF7 in pDCs and their IFN-α production. Although there are a number of reports showing the potential use of BAY11 in the treatment of malignancies through its inhibitory activity of NF-κB, the evidence linking it to autoimmune diseases is scant and there is no direct evidence so far that BAY11 prevents the activity of type I IFN-related diseases such as SLE. pDC activation in the blood by self-nucleic acids is regarded as a pathogenic trigger of the autoimmune process, and a dysregulated type I IFN elevation in serum by the continuous pDCs activation amplifies the pathogenic spiral in SLE [12–14]. On the basis of our current results showing that BAY11 inhibited the IFN-α production in PBMCs from SLE patients as well as from healthy donors, treatment with BAY11 may have the potential to attenuate the IFN environment and in turn to break off the pathogenic spiral in autoimmune diseases by limiting the disordered pDC function. Also, the experiments in injecting mice with poly U are suggestive of the agent's potential in inhibiting the inducible IFN response in vivo, though the serum IFN elevation is not pathophysiologically but artificially induced in our experimental setting.
Under normal physiological conditions, host-derived self-nucleic acids usually have little chance of encountering endosomal TLR7 and TLR9 because of their instability in relation to nucleases and by their location separate from endosomes. However, a breakdown in the innate tolerance to self-nucleic acids occurs when tissue injury or necrosis release some endogenous molecules, including antimicrobial peptide (LL37) and nuclear protein (high-mobility group box 1 protein; HMGB1), which help to promote stabilization and delivery of immune complexes into early endosomes [9, 41, 42]. Even in the current experiments using SLE sera and necrotic cell supernatant that perhaps comprise these molecules, BAY11 functions as an inhibitor of the pathogenic IFN-α response. Thus, our findings provide an opportunity for the development of therapeutic strategies that directly inhibit the pathogenic cellular and molecular components leading to SLE.
Also TNF-α production in pDCs was repressed by BAY11 at the high concentration, and accordingly the therapeutic window of BAY11 for selective interference with IFN-α was narrow. Since endogenous TNF-α limits the IFN-α production in pDCs , there is a possibility that the repression of TNF-α results in abating the inhibitory function of BAY11 against IFN-α production at high concentration. Thus, the most efficient and practical biological concentration may need to be decided from further studies.
At the downstream of TLR7/9-MyD88, the signaling pathway bifurcates into NF-κB- and IRF-7- activation pathways, which are responsible for the induction of proinflammatory cytokines and type I IFNs, respectively [2, 5]. Whereas IRF7 phosphorylation and nuclear translocation depend on IKKα, NF-κB activation needs IKKβ. IKKβ homodimer can compensate the function of heterodimer of IKKα and IKKβ in activating NF-κB in the absence of IKKα . Given the function of BAY11 as an inhibitor of IKK activity [18, 25], a more plausible explanation for its inhibitory activities in regards to both IFN-α and TNF-α in pDCs is that BAY11 targets IKKα in the inhibition of IFN-α and IKKβ in the inhibition of TNF-α at the downstream of TLR7/9-MyD88.
The other two IKK-related kinases, TANK-binding kinase 1 (TBK1) and IKKτ (also called as IKKε), are also reported to be involved in the phosphorylation of IRF-7 as well as IRF3 . However, CpG-induced IFN-α secretion is not impaired in mice deficient in TBK1 or IKKτ , indicating that these two IKKs are dispensable for TLR-mediated induction of IFN-α in pDCs. Similar to IKKα deficiency, IRAK1 deficiency leads to the defective transcriptional activation of IRF7 and defective production of IFN-α gene in pDCs , indicating a critical involvement of IRAK1 in the induction of type I IFNs in TLR7 and TLR9 signaling pathways. Although it is unclear at present how IKKα links to IRAK1, either kinase appears to be the gateway for activation of IRF7 to induce IFN-α production in pDCs and both could be potential targets for the treatment of autoimmune disorders. Further studies will be required to determine what the specific target of BAY11 is, whether BAY11 inhibits IRAK1 activationor the precise mechanism by which BAY11 inhibits the signaling pathway of TLR-mediated IFN-α production in pDCs.
In contrast to RNA-sensing receptor TLR7 in pDCs, another RNA-sensing cytosolic RIG-I-like receptor sensors in myeloid DCs through recognition of dsRNA such as poly IC can also induce IFN-α/β in an IPS-1-dependent manner . However, BAY11 was incapable of inhibiting the poly IC-induced IFN-α production by myeloid DCs. This finding can be explained by the evidence that, at the downstream of RIG/MDA5-IPS-1, both IKKα and IKKβ are dispensable for the type I IFN production [9, 32]. However, BAY11 could suppress the poly IC-induced IL-12 and TNF-α secretion by the myeloid DCs. This could also be explained by the evidence showing that TLR3-mediated production of proinflammatory cytokines is dependent on IKKβ during the signaling process of the TRIF-NF-κB pathway .
Collectively, our data demonstrated an antagonistic property of BAY11 to the in vitro and in vivo IFN response and imply a possibility for new therapeutic approaches by interference with the pathogenic components of autoimmune disorders. Thus, our findings provide a foundation for the exploitation of novel IFN inhibitors, and we here propose that a selective IKKα inhibitor designed to abrogate nuclear translocation of IRF7 and sequential type I IFN production would be a promising tool for the treatment of IFN-related diseases.
blood dendritic cell antigen
IFN regulatory factor 7
peripheral blood mononuclear cells
plasmacytoid dendritic cell
systemic lupus erythematosus
tumor necrosis factor.
The authors thank Ms Mihoko Inoue and Ms Hitomi Yoshimura for manuscript preparation. This work was supported by Grant-in-Aid of Scientific Research (21591289,60224325, 20390146 and 2006033) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid of The Japan Medical Association, and Takeda Science Foundation.
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