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Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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, IL-1, IL-6, and IL-12 (1). These cytokines are an important component of an innate immune response, but their production must be tightly regulated to prevent autoimmune pathologies. TNF- is one of the first cytokines to be produced after stimulation (2) and is followed closely by IL-1 and IL-6. The synthesis of IL-10 under these conditions usually comes after the induction of TNF- and IL-1 and is thought to prevent the overproduction of the inflammatory cytokines. For most of the inflammatory cytokines, the transcription factors that induce cytokine gene expression and the signal transduction pathways leading to cytokine production have been identified (3). The regulation of IL-10 remains less well understood.
IL-10 is a class II -helical cytokine and the founding member of a growing family of structurally related cytokines, which includes IL-19, IL-20, IL-22, IL-24, and IL-26. The binding of IL-10 to IL-10R1 induces a conformational change in the receptor, allowing it to dimerize with IL-10R2 leading to signal transduction in target cells (4). IL-10 is one of a small number of cytokines that have been well documented to have potent immune inhibitory capacity. IL-10 was originally called "cytokine synthesis inhibiting factor," and it can inhibit the transcription and translation of a variety of inflammatory cytokines (5). IL-10 exerts potent inhibitory effects on accessory cells, resulting in a reduction in Ag presentation and either an inhibition (6) or biasing of (7) T cell activation. The administration of exogenous IL-10 to macrophages can render them refractory to IFN-
(8) and diminish their responses to LPS (9).
We have previously shown that stimulation of macrophages in the presence of immune complexes (IC)3 induces the production of high amounts of IL-10 (8), and we demonstrated that activation of ERK was required but not sufficient for such event (10). In the present work, we examined the kinetics and the molecular mechanisms of IL-10 production. We show that the superinduction of IL-10, which occurs following stimulation of macrophages in the presence of IC, happens remarkably rapidly. Within minutes of stimulation, IL-10 pre-mRNA transcripts are detectable, and within an hour cytokine production can be measured in the supernatants. These kinetics are even more rapid than the production of TNF- in response to endotoxin (2). As we examined the chromatin modifications across the IL-10 promoter in resting and stimulated macrophages, we found that the rapid induction of cytokine synthesis depended not only on the activation of transcription factors, but also on a transient remodeling of the IL-10 promoter that occurs as a result of ERK activation. We herein describe a specific, rapid, and evanescent phosphorylation of histone H3 along the IL-10 promoter that correlates temporally with transcription factor binding and with IL-10 gene expression. These data reveal a critical role for chromatin phosphorylation in regulating IL-10 gene expression in macrophages.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The MEK/ERK inhibitor, PD98059, and the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), were obtained from Calbiochem (EMD Biosciences). Ultrapure LPS from Escherichia coli K12 strain was purchased from InvivoGen. Anti-phosphorylated histone H3 (Ser10) Ab, anti-acetylated histone H3 (Lys14), and anti-Sp1 Ab were obtained from Upstate. TRIzol reagent was purchased from Invitrogen Life Technologies. RNase-free DNase I and micrococcal nuclease (MNase) were obtained from Roche Diagnostics.
Mice
Six- to 8-wk-old BALB/c mice were purchased from Taconic Farms. All mice were maintained in HEPA (High Efficiency Particulate Air)-filtered Thoren units (Thoren Caging Systems) at the University of Maryland (College Park, MD). Mice were used at 6–10 wk of age as a source of bone marrow-derived macrophages (BMM
). All procedures were reviewed and approved by the University of Maryland Institutional Animal Care and Use Committee.
BMM and IC
BMM were prepared as described previously (11). Briefly, BM was flushed from the femurs and tibiae of mice, and cells were plated in petri dishes in complete medium, which consists of DMEM/F12 supplemented with 10% FBS, penicillin/streptomycin, glutamine, and 20% L cell conditioned medium. On days 2 and 5, cells were fed with complete medium. On day 7, cells were removed from petri dishes and cultured on tissue culture dishes in complete medium without L cell conditioned medium. On the next day, cells were subject to experimentation.
Rabbit polyclonal IgG to chicken egg albumin (anti-OVA IgG) was supplied by Cappel (MP Biomedicals). After the lyophilized powder was reconstituted, the contaminating endotoxin was removed by using EndoClean from BioVitage. Chicken egg albumin (OVA) was purchased from Worthington Biochemical Corporation and polymyxin B-agarose (Sigma-Aldrich) was used to remove LPS. IC consisting of IgG-OVA were prepared by mixing 181 µl of RPMI 1640 with 14 µl of chicken OVA (1 mg/ml) and 117 µl of anti-OVA IgG (4 mg/ml) for 30 min on a rotary platform at room temperature, as described (8).
Quantitative real-time PCR (QRT-PCR)
QRT-PCR was performed on an ABI Prism 7700 Sequence Detection System using SYBR Green PCR reagents purchased from Bio-Rad. Melting curve analyses were performed after PCR amplification to ensure that a single product with the expected melting curve characteristics was obtained, as described previously (10).
Cytokine measurement
Cytokines were measured by sandwich ELISA using Ab pairs provided by BD Pharmingen (IL-12p70, 9A5, and C17.8; IL-10, JES-2A5, and JES-16E3) according to the manufacturer’s instructions.
RNA isolation and RT-PCR
BMM (3–5 x 106 cells per reaction) were subjected to RNA extraction using TRIzol reagent. The contaminating DNA was then removed by RNase-free DNase I treatment. ThermoScript RT-PCR system (Invitrogen Life Technologies) was used to generate cDNA from RNA by using random hexamers or oligo(dT)20. QRT-PCR was used to measure both mature and premature IL-10 mRNA levels. Premature IL-10 mRNA was analyzed by using random hexamers-generated cDNA and the following primer pairs: sense, 5'-CATTCCAGTAAGTCACACCCA-3' (intronic primer), and antisense, 5'-TCTCACCCAGGGAATTCAAA-3', and GAPDH primer pairs: 5'-TGTTCCTACCCCCAATGTGT-3', and antisense, 5'-TCCCAAGTCACTGTCACACC-3' (intronic primer). Mature IL-10 mRNA was amplified by using oligo(dT)20-generated cDNA and the following primer pairs: sense, 5'-AAGGACCAGCTGGACAACAT-3', and antisense, 5'-TCTCACCCAGGGAATTCAAA-3', and GAPDH primer pairs: sense, 5'-TGTTCCTACCCCCAATGTGT-3', and antisense, 5'-GGTCCTCAGTGTAGCCCAAG-3'.
Chromatin immunoprecipitation (ChIP) assay
ChIP assays were performed following ultrasonic shearing conditions that result in relatively uniform DNA fragment size of 
300 bp. The remaining procedures were conducted as previously described (10). The primers used to amplify specific regions of the IL-10 promoter are listed in the table of Fig. 1. TNF- primers used for QRT-PCR were as follows: 5'-CCACATGAGATCATGGTTTTCTC-3' and 5'-CTGGCTAGTCCCTTGCTGTC-3'. IL-12p40 primers used for QRT-PCR were as follows: 5'-TTTCGACGTCTATATTCCCTCTG-3' and 5'-AGCTGCCTGGTCTGATGTG-3'. IL-12p35 primers used for QRT-PCR were as follows: 5'-CGACGCACTTGTCCTTGAGAT-3' and 5'-ACTGAGAGGAGCTGCTGGAT-3'. TdT primers used for QRT-PCR were as follows: 5'-ACCAAGACTGACAACCCACGTT-3' and 5'-GTGGCAGTCAGAGGCATCTTT-3'.
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MNase accessibility assay was performed on cells grown in 100-mm tissue culture dishes that were stimulated with LPS/IC. At different time intervals, formaldehyde was added for 15 min at room temperature at a final concentration of 1%, followed by glycine (0.125 M) to neutralize formaldehyde. Cells were washed and lysed in 4 ml of ice-cold Nuclei EZ lysis buffer (Sigma-Aldrich), centrifuged at 500 x g for 4 min, and the nuclei were resuspended with an additional 4 ml of ice-cold Nuclei EZ lysis buffer. Washed nuclei were pooled and resuspended in MNase digestion buffer (10 mM Tris-HCl (pH 7.4), 15 mM NaCl, 60 mM KCl, 0.15 mM spermine, and 0.5 mM spermidine). After centrifugation at 120 x g for 10 min at 4°C, the nuclei were resuspended in MNase digestion buffer containing 1 mM CaCl2. MNase was then added and incubated at room temperature for 5 min. The reaction was terminated by adding MNase stop buffer (100 mM EDTA and 10 mM EGTA in 10 mM Tris-HCl (pH 7.4)). Proteinase K (100 µg) and RNase A (10 µg) were then added and incubated at 37°C overnight. DNA was purified with phenol/chloroform extraction and ethanol precipitation. The purified DNA fragments were subjected to QRT-PCR analysis. DNase I accessibility was determined as described previously (10).
Western blotting analysis of histone H3 acetylation
BMM (3–5 x 106 cells per reaction) were treated with TSA for 1 h. The cells were lysed by whole-cell lysis buffer (20 mM Tris-HCl (pH 7.5), 0.15 M NaCl, 1% Triton X-100, and protease inhibitor and phosphatase inhibitor mixtures). After sonication, equal amounts of whole-cell lysate were subjected to SDS-PAGE analysis. Western blotting assay was then performed to detect histone H3 acetylation using rabbit polyclonal anti-acetylyl-histone H3 Ab (06-599) and mouse monoclonal anti-histone H3 Ab (05-499) (Upstate Biotechnology).
Data analysis
The relative differences among samples were determined using the 
CT methods as described in the Applied Biosystems protocol. A CT value was determined for each sample using the CT value from input DNA to normalize ChIP assay results. The CT value for GAPDH was used to normalize loading in the RT-PCRs. For the MNase or DNase I accessibility assays, CT values were determined by subtracting the CT value from each MNase or DNase I concentration from the zero enzyme control CT value. A CT value was then obtained by subtracting control CT values from the corresponding experimental CT. The CT values were converted to fold difference compared with the control by raising 2 to the CT power. Student’s t test was used for statistical analysis. Values of p < 0.05 were considered to be statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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We previously demonstrated that the stimulation of macrophages with TLR agonists (LPS) combined with IC resulted in the production of large amounts of IL-10 (11). This superinduction of IL-10 was due, in part, to the activation of the MAPK pathway (10). In the present work, we quantitatively and spatiotemporally analyzed changes in histone H3 phosphorylation across the promoter region of the IL-10 gene following stimulation. We generated chromatin fragments with an average size of 300 bp (Fig. 1), which in combination with QRT-PCR allowed a high resolution profiling of histone modifications across the first 1600 bases of the IL-10 promoter.
Macrophages were stimulated with LPS plus IC and the phosphorylation of histone H3 at Ser10 along the promoter region of the IL-10 gene was analyzed by ChIP. Initially, we examined the second nucleosome from the transcription start site, because this is the location of the binding site to the transcription factor Sp1 (12). Phosphorylation of histone H3 at this site is rapid and peaks within 30 min of stimulation (Fig. 2A). This peak of histone phosphorylation is remarkably transient and is reduced to baseline levels by 60 min poststimulation (Fig. 2A). We performed a similar analysis to quantify phosphorylation over the entire proximal 1600 bp of the IL-10 promoter. Although there was a substantial increase in histone phosphorylation throughout much of this region following stimulation, there were clear differences in the degree to which individual nucleosomes were modified. The highest degree of phosphorylation was observed at regions corresponding to the first two nucleosomes, but regions corresponding to nucleosomes –4 and –6 were also phosphorylated with similar kinetics (Fig. 2A and unpublished data). These regions correspond to segments of the IL-10 promoter that are binding sites to the transcription factors implicated in IL-10 gene expression (13). The distal-most segments analyzed, which correspond to nucleosomes –12 and –11, were not phosphorylayted to any substantial degree, nor were some of the intermediate nucleosomes, e.g., –3, –7 (Fig. 2A and unpublished data). Thus, there appears to be a rapid and transient phosphorylation of nucleosomes across the IL-10 promoter in stimulated cells. These phosphorylation events do not appear to be random, but rather generally correspond to, or are adjacent to, segments of the promoter that bind to transcription factors.
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). The negligible degree of histone H3 phosphorylation and acetylation in resting cells was similar for three different cytokines analyzed (IL-10, IL-12, and TNF-) and comparable to the lymphocyte-specific TdT gene that is not expressed in macrophages (14) (Fig. 2C). Acetylation of histone H3 at Lys14 on the IL-10 promoter
The acetylation of histones is an important modification that has been implicated in controlling gene expression (15). We examined the acetylation of histone H3 at Lys14 across the IL-10 promoter region over time. Although low levels of transient lysine acetylation of histone H3 at nucleosome 2 were detectable within the first 15 min of stimulation, the main peak of acetylation was not detected until 60 min after stimulation (Fig. 3A). By 120 min, this peak of acetylation had returned to baseline. The pattern and extent of acetylation was distinct from that observed with phosphorylation (Fig. 3B). The extent of acetylation at nucleosome 2 was modest relative to the extent of phosphorylation, and there were low levels of acetylation spanning a broad region corresponding to nucleosomes –3 to –8. There was no detectable acetylation at the distal regions of this promoter. Importantly, the peak of acetylation did not occur until 60 min after stimulation, a time by which the phosphorylation of histones was returning to baseline.
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Because Sp1 has been shown to play an important role in the regulation of IL-10 gene expression (12) and because this area of the promoter was rapidly phosphorylated, we assessed the kinetics of Sp1 recruitment to the IL-10 promoter. Macrophages were stimulated with LPS plus IC, and then Sp1 was immunoprecipitated for ChIP and analyzed over time. Sp1 could not be detected on the promoter for the first 30 min poststimulation. After this lag, however, Sp1 was rapidly recruited to the promoter, reaching a peak at 45 min posttreatment and gradually declining thereafter (Fig. 4A). The recruitment of Sp1 was highest in the area surrounding the Sp1 binding site (5'-GGAGGAGGAGCC-3') in the nucleosome 2 (–196 to –76 bp); however, there was also a significant degree of Sp1 recruitment to the area corresponding to nucleosome 5 (–594 to –417 bp) that contained two potential Sp1 binding sites (5'-CTGCCCCACAGCAC-3'; 5'-AAAATCAGCCCTCT-3') (Fig. 4B). Importantly, the kinetics of Sp1 recruitment to the area corresponding to nucleosome 2 temporally followed the phosphorylation of histone H3 at this site (see Fig. 2A).
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We next compared the kinetics of histone modifications with the induction of IL-10 transcription. To do this we measured the levels of premature nuclear mRNA. This premature mRNA contains introns, and therefore the amplification of mRNA using an intron-specific primer can be used as an indicator of gene transcription (16). IL-10 pre-mRNA accumulation in macrophages treated with LPS plus IC was rapid and dynamic. It was detectable by as early as 15 min, and it peaked at 45 min poststimulation. By 120 min after stimulation, pre-mRNA levels had receded to background levels. As expected, mature IL-10 mRNA accumulation took slightly longer to be produced and it persisted longer (Fig. 5).
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We previously reported that maximal IL-10 production by macrophages depended on ERK activation (10), which has also been recently reported in RAW 264.7 cells (17). In the present work, we examined the levels of histone H3 phosphorylation and Sp1 recruitment to the IL-10 promoter following treatment of cells with PD98059, an inhibitor of ERK activation. Treatment of macrophages with PD98059 resulted in a substantial loss of histone H3 phosphorylation (Fig. 8). Sp1 recruitment was also dramatically reduced after treatment with PD98059 (Fig. 8). These data are consistent with the hypothesis that ERK activation leads to the phosphorylation of chromatin at the IL-10 promoter, allowing the recruitment of Sp1 to the promoter.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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This work suggests that the transcription of an anti-inflammatory cytokine, such as IL-10, is regulated by a more complex mechanism than the inflammatory cytokines, such as TNF-. In addition to transcription factor activation, a second level of regulation occurs at the level of chromatin. The speed and specificity of this second level of regulation are quite remarkable. The covalent modifications to histones occur within minutes of stimulation and they are reversed almost as quickly. The specificity of these modifications was also unexpected. Not only were these alterations specific to IL-10 and not to any of the other inflammatory cytokines examined, but also segments of the IL-10 promoter located only 500 bases away from highly modified regions underwent no detectable phosphorylation changes throughout the observation period. As far as we are aware, this type of regulation has not been reported for any other cytokine to date.
There are aspects of this regulation that closely resemble the "nucleosome response" previously reported by Mahadevan and colleagues (19). In a series of studies, this group demonstrated that the nucleosome response is initiated by the activation of the MAPK cascade in response to cellular stressors. This leads directly to immediate-early gene expression. This gene expression occurs in the absence of de novo protein synthesis (20), and in some cases the transcription factors are already associated with their respective DNA binding elements (19). We show that a similar cellular response occurs when macrophages encounter IC. The histones are similarly phosphorylated in response to MAPK activation. However, in the case of IL-10, this phosphorylation does not result in gene expression. Macrophages exposed to IC alone produce no IL-10, despite the activation of ERK and the phosphorylation of histones. Rather, transcription of the IL-10 gene requires a second set of signals provided by TLR stimulation. This stimulation activates the necessary transcription factors, allowing them to bind to the phosphorylated chromatin that is now accessible to them (Fig. 10). Thus, the induction of this anti-inflammatory cytokine is more complex than many of the inflammatory cytokines, whose synthesis mainly requires the recruitment of transcription factors and histone acetylation (21, 22).
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Similar to previous studies with other genes and other systems (31, 32), the acetylation of histone H3 at the IL-10 promoter follows histone H3 phosphorylation. Unlike many of these other systems, however, this modification does not appear to coincide with transcriptional activation. First, transcription factors bind to the promoter before acetylation occurs, and are in fact released from the promoter by the time that acetylation peaks. Second, the production of IL-10 pre-mRNA transcripts climaxes and declines before histone acetylation crests. Finally, treating macrophages with HDAC inhibitors does not affect IL-10 production. Thus, whereas histone H3 phosphorylation temporally correlates with IL-10 gene expression, acetylation does not.
Our results predict that the phosphorylation of histones is tightly associated with transcriptional activation of the IL-10 gene. In other cellular systems, the phosphorylation of histones is not always associated with gene activation. In fact, histone H3 is highly phosphorylated on serine 10 on condensed chromatin during mitosis (23). Unlike the phosphorylation events associated with mitosis, however, the IC-induced phosphorylation that we observe is specific to individual regions of the IL-10 promoter rather than uniform, and it is far more transient. Studies are underway to identify the kinase(s) responsible for histone phosphorylation, and the phosphatase(s) mediating the rapid dephosphorylation of histones following activation. We predict that mechanisms to prolong histone phosphorylation may be exploited to manipulate macrophage IL-10 production.
In summary, we provide a detailed analysis of the modifications of the nucleosomes associated with the promoter region of IL-10 gene. We show that the evanescent, ERK-dependent, phosphorylation of histone H3 at Ser10 is essential for IL-10 superinduction. These studies provide a molecular understanding of IL-10 gene regulation in macrophages, which may lead to novel ways to manipulate IL-10 levels. Because the production of high levels of IL-10 can either result in a beneficial anti-inflammatory response, or a pathological immunosuppressive response, new ways to manipulate the production of this cytokine can be used to enhance or inhibit immune responses, as necessary.
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Acknowledgments |
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Disclosures |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Footnotes |
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1 This work was supported in part by National Institutes of Health Grant AI49383. 
2 Address correspondence and reprint requests to Dr. David M. Mosser, Department of Cell Biology and Molecular Genetics, 1103 Microbiology Building, University of Maryland, College Park, MD 20742. E-mail address: dmosser{at}umd.edu
3 Abbreviations used in this paper: IC, immune complex; HDAC, histone deacetylase; TSA, trichostatin A; MNase, micrococcal nuclease; BMM, bone marrow-derived macrophage; QRT-PCR, quantitative real-time PCR; ChIP, chromatin immunoprecipitation.
Received for publication March 1, 2006. Accepted for publication April 26, 2006.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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receptors. J. Immunol. 168: 3697-3701. R ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175: 469-477. receptor type I. J. Exp. Med. 188: 217-222. 
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in mouse macrophages. Cell Signal. In press.B recruitment. Nat. Immunol. 3: 69-75. [Medline]This article has been cited by other articles:
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K. J. Mylonas, M. G. Nair, L. Prieto-Lafuente, D. Paape, and J. E. Allen Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing J. Immunol., March 1, 2009; 182(5): 3084 - 3094. [Abstract] [Full Text] [PDF]
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J. P. Edwards, X. Zhang, and D. M. Mosser The Expression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor by Regulatory Macrophages J. Immunol., February 15, 2009; 182(4): 1929 - 1939. [Abstract] [Full Text] [PDF]
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J. Leng, B. A. Butcher, C. E. Egan, D. S. Abi Abdallah, and E. Y. Denkers Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation J. Immunol., January 1, 2009; 182(1): 489 - 497. [Abstract] [Full Text] [PDF]
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T. L. Bonfield, M. J. Thomassen, C. F. Farver, S. Abraham, M. T. Koloze, X. Zhang, D. M. Mosser, and D. A. Culver Peroxisome Proliferator-Activated Receptor-{gamma} Regulates the Expression of Alveolar Macrophage Macrophage Colony-Stimulating Factor J. Immunol., July 1, 2008; 181(1): 235 - 242. [Abstract] [Full Text] [PDF]
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S. Garrett, K. Dietzmann-Maurer, L. Song, and K. E. Sullivan Polarization of Primary Human Monocytes by IFN-{gamma} Induces Chromatin Changes and Recruits RNA Pol II to the TNF-{alpha} Promoter J. Immunol., April 15, 2008; 180(8): 5257 - 5266. [Abstract] [Full Text] [PDF]
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B. G. Brem-Exner, C. Sattler, J. A. Hutchinson, G. E. Koehl, K. Kronenberg, S. Farkas, S. Inoue, C. Blank, S. J. Knechtle, H. J. Schlitt, et al. Macrophages Driven to a Novel State of Activation Have Anti-Inflammatory Properties in Mice J. Immunol., January 1, 2008; 180(1): 335 - 349. [Abstract] [Full Text] [PDF]
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S. L. Lambert and O. M. Martinez Latent Membrane Protein 1 of EBV Activates Phosphatidylinositol 3-Kinase to Induce Production of IL-10 J. Immunol., December 15, 2007; 179(12): 8225 - 8234. [Abstract] [Full Text] [PDF]
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) or acetylated (
