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Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294, and
Department of Rheumatology and General Internal Medicine, University of Leiden Medical Center, Leiden, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R expression on the same cells (1, 2, 3).
IL-10 enhances B cell survival, proliferation, differentiation, and Ab
production, and these effects appear to play a role in autoimmune
diseases (1, 3, 4, 5, 6, 7). Several studies have shown that unaffected family members of systemic lupus erythematosus (SLE)3 patients produce high levels of IL-10 and that first-degree relatives of nonsurvivors of fatal meningococcal disease produce significantly lower levels of IL-10 than relatives of survivors (8, 9, 10). The implication of a heritable genetic basis for IL-10 production is supported by the concordance of IL-10 production in monozygotic twins, which suggests that genetics could account for up to 75% of IL-10 production (10). Indeed, the high IL-10 production associated with autoimmune diseases including rheumatoid arthritis (RA) and SLE may be a genetic risk factor for disease susceptibility (2, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19).
The basis for heritable differences in IL-10 production is not known. The IL-10 gene promoter is polymorphic, and promoter-reporter studies have identified several positive and negative regulatory promoter sequences within the 1.3 kb region upstream of the transcription start site (20, 21, 22, 23). Two CA-repeat microsatellites, IL-10.R and IL-10.G, -4 kb and -1.1 kb, respectively (24, 25), and three single nucleotide polymorphisms (SNP) at -1082 (G/A), -819 (C/T), -592 (C/A) upstream of the transcription start site have also been identified (26).
Variable associations between the proximal IL-10.G microsatellite alleles and IL-10 production and between SNPs or SNP haplotypes in the 1.4 kb IL-10 proximal promoter region and IL-10 production have been reported (27, 28, 29, 30, 31, 32, 33). Similarly, the associations between IL-10.G alleles and SLE and RA (28, 29, 30, 31), between SNP haplotypes in the proximal IL-10 promoter and SLE, and between IL-10 SNP haplotypes and disease severity have been inconsistent (32, 33, 34, 35). These results, coupled with the recent data indicating a relationship between alleles of the more distal IL-10.R microsatellite and IL-10 production suggested the possibility that other more distal promoter elements may be involved in IL-10 production. To identify additional SNPs that might affect IL-10 production, we have examined the -1.3 kb to -4 kb region of the IL-10 promoter from normal donors phenotyped for high or low levels of IL-10 production. Our results indicate that at least seven novel SNP sites exist in the distal region of the IL-10 promoter and that distal SNP haplotypes associate with quantitative IL-10 production. Our results also show that one of the novel SNP alleles associates with SLE in an African-American cohort and may be a risk factor for SLE in this group.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fifty-two normal Caucasian donors, characterized for quantitative IL-10 production (36), provided genomic DNA for genotyping. An additional 128 normal Caucasian donors from the Leiden University Medical Center (Leiden, The Netherlands) blood donor service provided genomic DNA to confirm genotype frequencies. Sixty-four African-American normal donors and 60 African-American SLE patients from the University of Alabama (Birmingham, AL) also provided DNA for analysis. All studies were approved by the respective Institutional Review Boards, and donors provided written informed consent. All SLE patient donors met the revised American College of Rheumatology criteria for systemic lupus (37).
IL-10 production
Determination of IL-10 production in LPS-stimulated whole blood assays is described elsewhere (36). Briefly, whole blood samples were diluted 1:1 with RPMI 1640 (Life Technologies, Paisley, U.K.). LPS (Escherichia coli 0111; B4, Boivin method; Difco, Detroit, MI) was added to a final concentration of 1 µg/ml and cells were stimulated for 24 h at 37°C under 5% CO2 atmosphere. Determination of IL-10 concentrations by ELISA (BioSource, Fleurus, Belgium) was performed according to the manufacturer’s guidelines.
PCR amplification and sequencing
DNA was extracted from whole blood using standard molecular
techniques. Forward and reverse primers used to PCR-amplify and
sequence the 4.1-kb region of the IL-10 promoter (GenBank accession
number AF295024) are given in Table I
.
Primers were purchased from Life Technologies or from the
Oligonucleotide Synthesis Core Facility at the University of Alabama.
PCR amplifications were performed using the Expand Long Template PCR
System and the manufacturer’s suggestions (Roche Diagnostic Systems,
Indianapolis, IN), or recombinant Taq polymerase and
deoxynucleoside triphosphates from Life Technologies (Grand Island,
NY). Primers IL-10UPP and IL-10LWR (Table I) were used to PCR amplify a
4.1-kb fragment of the IL-10 gene containing 4.057 kb of the
5'-untranslated region (UTR) and 43 bases of the open reading frame.
Typically, 125 ng of genomic DNA template were used in a 50-µl PCR
performed in a Perkin-Elmer (Norwalk, CT) 9600 Thermal Cycler.
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For genotyping of populations at the more common SNP sites, primers
IL-10UPP and IL-10S9R were used to amplify a 1.443-kb IL-10 promoter
fragment containing the -3575, -2849, and -2763 SNP sites.
Gel-purified DNA fragments were sequenced using S6F and S9R primers
(Table I
).
Cloning of IL-10 promoter segments
For extended SNP haplotype determination the 4.1-kb IL-10
promoter fragments were cloned into pGEM-T vector (Promega, Madison,
WI). Plasmids were propagated in E. coli DH5
and plasmid
DNA purified from bacterial cultures using the QIAprep Spin Miniprep
Kit (Qiagen).
All DNA sequence comparison alignments were performed using DNAstar SeqMan or MegAlign programs (DNAstar, Madison, WI). DNA sequence motif searches for putative transcription factor binding sites were performed using TESS, MatInspector V2.2 and TFSEARCH web-based search programs (www.cbil.upenn.edu/tess/).
IL-10 mRNA determination
mRNA was isolated from pelleted whole blood cultures after
stimulation with LPS for 18 h. mRNA (15–20 ng) was separated in
1% agarose, blotted onto Hybond N membrane and probed for 18 h at
42°C using a 0.7-kb BglII-HindIII,
32P-labeled DNA fragment of IL-10 (pH15C, no.
68192; American Type Culture Collection, Manassas, VA). Washed blots
were exposed to Biomax film (Eastman Kodak, Rochester, NY) and band
intensities quantified relative to GAPDH mRNA using a phosphor-imaging
system (Molecular Dynamics, Sunnyvale, CA). For mRNA half-life studies,
semiquantitative PCR was used. For this method, mRNA was isolated from
cultures treated with actinomycin D and cDNA was synthesized. mRNA
levels were quantified relative to an internal 
-actin standard as
described (38). PCR products were separated on agarose gel
and quantified by ethidium bromide staining using an Eagle Eye II
(Stratagene, La Jolla, CA).
Statistical analysis
The 
2 test was used to compare
differences in the distributions of phenotypes and allele frequencies.
A p value of 0.05 was used to reject the null
hypothesis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The production of IL-10 by peripheral blood leukocytes from disease-free, normal volunteers in response to an LPS stimulus was determined by the standardized assay, previously described (36). Twenty-six donors with low IL-10 production and twenty-six donors with high IL-10 production were chosen for further study from the upper and lower quartiles of a population of 163 phenotyped normal donors. Each was genotyped for SNPs in the proximal 1.3-kb promoter (-1330G/A, -1082G/A, -819C/T, -592C/A). To explore the possibility of additional novel SNPs within the proximal 1.3-kb promoter in these phenotyped donors, genomic DNA from 12 donors, 6 chosen randomly from each group, was sequenced in both directions. No additional SNPs were identified.
Identification of novel IL-10 promoter polymorphisms
To identify SNPs in the more distal promoter region that might
correlate with IL-10 production, we PCR amplified a 4.1-kb DNA fragment
from the IL-10 promoter, which included the 5'-UTR and 43 bases of the
open reading frame. Eight low and six high IL-10-producing Caucasian
donors were selected and the promoter region between -1.3 kb and -4
kb sequenced. DNA sequences obtained using the BigDye Terminator Cycle
Sequencing system were confirmed by sequencing the reverse strand using
the M13-based Dye Primer system. Seven novel genetic SNPs were
identified within the -1.3 kb to -4 kb promoter region of IL-10 (Fig. 1) and the frequencies of these SNPs were
characterized in two independent populations (Fig. 1, see below). At
three of these sites (-3575T/A, -2849G/A, -2763C/A) both alleles are
commonly represented in the populations studied. At each of the other
four sites (-3715 A/T, -2776 A/G,
-2100C/A, -2050G/A) one allele (in bold)
predominates while the other rare allele has a frequency <5%.
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Determination of distal SNP haplotypes
The proximal SNPs in the IL-10 promoter (-1082G/A, -819C/T,
-591C/A) form three haplotypes in Caucasians (GCC, ACC, and ATA), and
a fourth haplotype (GTA) has been reported in Southern Chinese
(35). To determine the distal IL-10 promoter SNP
haplotypes for the three sites with common polymorphisms, we genotyped
the first cohort of 52 Caucasian donors. Four haplotypes were observed
in donors homozygous at all three sites or heterozygous at only one
site. To identify other possible haplotypes that may exist, we cloned
the 4-kb promoter from 19 donors heterozygous at more than one of the
common distal SNP sites. PCR-amplified promoter products were cloned
into pGEM-T vector and 10 randomly chosen clones from each donor
sequenced. Of the eight possible distal promoter SNP haplotypes, we
identified six haplotypes in our first group of 52 Caucasian normal
donors (Fig. 2). In this cohort, three
haplotypes comprised of the common distal SNPs (TGC, AAA, and AGA),
were present with the highest frequency (0.51, 0.26, and 0.13,
respectively) while the other haplotypes, TAA, AAC, and AGC, were
present with a low frequency (0.02, 0.05, and 0.04, respectively). In
our second, independent Caucasian cohort and in our African-American
populations (see below), we were able to unambiguously deduce the other
two possible distal SNP haplotypes (TGA and TAC; Fig. 2). Therefore,
all eight haplotypes for the three distal sites with common alleles
(-3575T/A, -2849G/A, -2763C/A) exist in normal populations.
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IL-10 mRNA and protein production in response to an LPS stimulus
were determined in high and low IL-10-producing donors as described in
Materials and Methods. Relative to GAPDH, the IL-10 mRNA
level was consistently higher in high IL-10-producing individuals
compared with low IL-10-producing individuals (Fig. 3, a and c). mRNA
half-life determinations were comparable (Fig. 3, b and
d), indicating that differences in IL-10 mRNA levels in this
system are independent of mRNA stability.
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We examined the genotype distribution in our normal phenotyped
Caucasian donors to determine whether any haplotypes were associated
with IL-10 production. Table II shows
that among the three most common haplotypes, both AAA and AGA were each
more frequently found in the low compared with the high IL-10 producers
(AAA in 35% of low vs 17% of high producers; AGA: 19% of low vs 6%
of high producers. Thus, the A-[G/A]-A haplotype was much more likely
in IL-10 low producers (p < 0.003). More
importantly, donors with two A-[G/A]-A haplotypes were 10-fold more
frequent among the 26 low compared with the 26 high producers (42% vs
4%; p < 0.007; Fig. 4).
Therefore, we extended this analysis by further dividing our
low-producing donors into two nonoverlapping groups based on
quantitative IL-10. Among donors in the lower half, which had a median
IL-10 production of 543 pg/ml, an A-[G/A]-A haplotype was more
frequent than among those in the upper half, which had a median
production of 903 pg/ml (73% vs 35%, p = 0.012). The
occurrence of two A-[G/A]-A haplotypes was also more common in the
lower than in the upper half; despite the small sample size of 13 in
each group, this distribution was statistically significant
(p = 0.044). Not surprisingly, the TGC
haplotype was significantly associated with high IL-10 production
(p < 0.05).
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Previous work has suggested that there may be association of
proximal SNPs and SNP haplotypes with IL-10 production (26, 31, 33), and we considered the possibility that an extended SNP
haplotype might show a stronger relationship to IL-10 production than
the distal SNP haplotype alone. Therefore, we constructed extended
haplotypes based on analysis of genotypes in homozygous donors or
donors with a single heterozygous site and on analysis of direct
sequence information of cloned promoter products. We identified nine
extended haplotypes that include both the proximal and the distal IL-10
promoter SNPs (Fig. 2). Within these extended haplotypes, the TGC
distal haplotype is linked to all three proximal haplotypes. However,
among the 104 DNA strands analyzed, both the AAA and AGA distal
haplotypes were found only with the AGCC proximal haplotype.
Conversely, the GATA proximal haplotype was found exclusively with the
TGC distal haplotype.
As predicted from the distributions of the AAA and the AGA haplotypes
and the absolute linkage of AGCC with these haplotypes in our
population, the AAA-AGCC and AGA-AGCC haplotypes predominated in the
low producer group (54% vs 23% in high producers, p
< 0.003). A distribution analysis of the AGCC proximal haplotype alone
also showed a higher frequency in the low producer group (low, 65%;
high, 44%) but this distribution did not show as marked a difference
between low and high IL-10 producers because of the TGC-AGCC, TAA-AGCC,
and AAC-AGCC haplotypes, most of which were found in the high producer
group. Indeed, if the proximal AGCC were predominantly responsible for
the IL-10 production phenotype, then the distribution of distal
haplotypes associated with AGCC should be the same in both high and low
producers. Table III shows that, with
AGCC held constant, the distal haplotypes do not occur with equal
frequency in both high and low producers. The A-[G/A]-A distal
haplotypes are much more frequently found in the low producers (82% vs
52%; p = 0.032).
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SNP allele distributions in SLE patients
To determine whether genetically determined capacity for IL-10
production might constitute a susceptibility factor for SLE, we
examined the distal SNP haplotypes of 24 SLE patients and compared the
distribution of these haplotypes to our high and low IL-10-producing
normal donors. The distribution of SLE patient haplotypes was
significantly different from low production normal donors
(p = 0.001) and essentially the same as the
high producers (Table IV).
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).
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shows that while there was no significant difference in the genotype
distribution at the first two sites, there was a significant difference
between normal donors and SLE patients at -2763
(p < 0.05). As with our normal donors
producing high levels of IL-10, the -2763A allele frequency was lower
and there were significantly fewer -2763A homozygotes in SLE patients
vs ethnically matched controls (5 in SLE, 16 in normal donors,
p = 0.026).
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The lack of an effect of SNP -3575 in our SLE patients was
initially puzzling. However, inspection of the normal African-American
population at this site revealed a very high frequency of TT
homozygosity and low frequency of AA homozygosity compared with
Caucasian normal donors. Indeed, the -3575T allele frequency in our 64
African-American normal donors was significantly different not only
from our Caucasian IL-10-low normal donors (0.84 vs 0.40) but also from
our Caucasian IL-10-high producers (0.84 vs 0.65; p <
0.00001 and p < 0.013, respectively). To determine
whether this might be related to the selection of these donors on the
basis of IL-10 phenotype, we genotyped a second population of 128
randomly selected Caucasians. The genotype distributions at positions
-3575 and -2763 between African-Americans and Caucasians were
significantly different (p < 0.00002 and
p < 0.03, respectively; Table VII). In particular, the -3575T allele
frequency was significantly higher in the African-American
normal donors (0.84 vs 0.69; p < 0.0001). This
enrichment for -3575T and under-representation of -3575A, a genotype
associated with high IL-10 production, in African-American normal
donors compared with Caucasians suggests that heritable differences in
IL-10 production capacity may represent one of the risk factors for the
increased prevalence of lupus in African-Americans.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies have found associations between the IL-10 promoter
microsatellites and IL-10 production and between the proximal promoter
SNPs and IL-10 production (27, 31, 33, 40). Given the
variability found in these studies, differences in cell type and
experimental conditions could explain these differences. Our data
strongly suggest that an additional explanation is more likely, that
is, that other promoter SNPs may influence promoter activity. We have
found that several novel alleles and haplotypes, defined by -3575 and
-2763 SNPs, associate strongly with IL-10 production. Specifically,
the T-G-C distal haplotype is associated with high IL-10 production and
the A-G/A-A distal haplotypes associate with low IL-10 production. The
physical linkage of the T-G-C distal haplotype with all three proximal
haplotypes in Caucasians might explain the variability between proximal
IL-10 haplotypes and IL-10 production seen in other studies. However,
because the association between the distal haplotypes and IL-10
production is not absolute (Fig. 4), additional factors or additional
SNP sites, perhaps as part of even longer extended haplotypes, may also
underlie some of the variation in IL-10 production levels.
Nonetheless, our studies suggest that the distal SNPs have important biological significance. Not only do these SNPs segregate significantly with IL-10 production in normal donors, but they also segregate with autoimmune disease. High IL-10 production is associated with the pathogenesis of autoimmune diseases in humans and in mouse models (1). IL-10 production is increased in RA and SLE patients in vivo and in monocytes and B-cells isolated from SLE patients and studied ex vivo (5, 8, 11, 12, 14, 15, 16, 17, 18, 19). IL-10 can prevent spontaneous cell death of germinal center B-cells by inducing Bcl2 expression and results in increased production of autoantibodies by B-cells from SLE patients (4, 5). Our data indicates that there is a significant difference in the genotype distribution at -3575 and -2763 between normal donors and African-Americans with SLE, which implicates high IL-10 production in disease susceptibility.
Of course, one explanation for positive disease associations is population admixture and genetic heterogeneity, which reflects different prevalent genotypes in different ethnic groups. Indeed, our data show that Dutch Caucasian and African-American normal donors differ significantly in the SNP allele distributions. African-Americans show a much higher allele frequency of -3575T, which is associated with high IL-10 production, and it is interesting to speculate whether this difference may underlie, in part, the higher susceptibility of African-Americans to SLE. In such a case, it is also interesting to consider what control group is most appropriate when analyzing IL-10 SNPs in African-American SLE patients. Use of African-American controls would miss the potential importance of -3575T in IL-10 biology since the allele frequency is the same in normal donors (0.83) and in SLE (0.83). Use of the Dutch Caucasian controls would make the role of -3575T clear. In either case, compared with either control group, the significant under-representation of the -2763 AA homozygous genotype in African-American SLE patients indicates that genetically determined differences in IL-10 production contribute to SLE susceptibility as a prototypic autoimmune disease.
The perspective that different ethnic groups may differ in IL-10 genetics is supported by several recent reports. Although not accompanied by functional analysis, the SNP at -3575 was recently reported in normal Italian donors (41). The -3575T allele frequency was higher in the Italian population (0.75) than in our Dutch cohort (0.61) although not as high as in our African-American population (0.83). The rare SNPs at -2050 and -2776 were also noted, but interestingly other positions at nt -2769, -1349, -1255, -851, and -657 were polymorphic in Italian normal donors but not in either our Caucasian or African-American groups. These data indicate the presence of genetic heterogeneity within and between ethnic groups in the highly polymorphic IL-10 promoter and raise the possibility that, in different populations, different SNPs or SNP haplotypes may be important in regulating the expression of IL-10.
Promoter SNPs alter cytokine gene transcription in other systems. The
-238 G/A and -308 G/A transitions in the TNF- promoter affect
transcription factor binding and expression of reporter genes, and
associate with cytokine production and disease outcome in psoriasis
(-238) and cerebral malaria (-308) (42, 43, 44, 45). Similarly,
the -81A/G and -590 C/T substitutions in the IL-4 promoter affect
binding of nuclear transcription factors and result in higher levels of
reporter gene expression (46, 47). The -590 SNP also
associates with higher serum IgE levels in asthma
(46).
Although posttranscriptional regulation by 3'-UTR elements has been shown in some systems (48), IL-10 message levels from high and low IL-10 producers show comparable half-lives but marked differences in quantity in our system. These observations support transcriptional regulation of IL-10 expression.
Many putative transcription factor binding sites exist throughout the 4-kb promoter region (21, 23, 49, 50, 51, 52). For example, within the proximal promoter region, the -1082 SNP appears within a putative ETS-factor binding site, while the -592 SNP may be a STAT3 binding site (20, 33). In the distal promoter region the -3575 SNP occurs within a putative Pit-1 binding site. Given the association between female sex hormones and SLE, and the high female to male ratio (9:1) in the disease, it is noteworthy that expression of isoforms of Pit-1 is regulated in part by estrogen, and that estrogen regulates IL-10 expression in PBMC from SLE patients (53). The -2763 SNP lies within putative lymphocyte-specific factor and myeloid zinc finger binding sites.
Nonetheless both genetic and nongenetic factors must contribute to IL-10 production. Using studies of IL-10 production by monozygotic twins and first-degree relatives of meningococcal patients, Westendorp et al. (10) showed that genetic factors account for as much as 75% of interindividual differences in IL-10 production. This suggests that up to 25% of IL-10 production can be accounted for by environmental factors, and data showing that Icelandic SLE patients and their spouses had significantly higher numbers of IL-10-producing cells than unrelated controls support this conclusion (54).
In summary, we have identified seven novel SNPs in the distal region of the IL-10 promoter in individuals phenotyped for IL-10 protein production and have determined the existence of eight distal promoter SNP haplotypes. We have shown that extended promoter SNP haplotypes, which include distal SNPs as well as proximal promoter SNPs, segregate significantly with quantitative IL-10 production and that distal SNPs that associate with IL-10 production significantly associate with SLE in African-Americans. This study provides the basis for a replication study of distal IL-10 promoter genetic variants in larger African-American cohorts and other ethnic groups.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert P. Kimberly, Division of Clinical Immunology and Rheumatology, University of Alabama, 1530 3rd Avenue South, Birmingham, AL 35294-0006.
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; RA, rheumatoid arthritis; UTR, untranslated region.
4 GenBank sequence X78437 lacks six nucleotides (GCTCAA) at position -1468 and two nucleotides (GA) at position -1684. These nucleotides were present in 28 donor sequences from two ethnic groups and in GenBank sequence U16720. Other non-SNP single nucleotide differences, deletions and insertions were present in the GenBank sequences relative to our consensus IL-10 sequence from both ethnic groups.
Received for publication August 17, 2000. Accepted for publication January 3, 2001.
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and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation. J. Immunol. Methods 218:63.[Medline]
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