Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjögren's syndrome
© Yoshimoto et al.; licensee BioMed Central Ltd. 2011
Received: 11 March 2011
Accepted: 21 October 2011
Published: 21 October 2011
In this study, we investigated possible aberrations of monocytes from patients with primary Sjögren's syndrome (pSS). We focused on B-cell-activating factor of the TNF family (BAFF) and IL-6 because they are both produced by monocytes and are known to be involved in the pathogenesis of pSS.
Peripheral monocytes were prepared from both pSS patients and normal individuals. The cells were stimulated in vitro with IFN-γ, and the amounts of IL-6 and soluble BAFF (sBAFF) produced by the cells were quantitated. The effect of sBAFF itself on the production of IL-6 was also studied. To investigate the response of pSS monocytes to these stimuli, the expression levels of the genes encoding BAFF receptors and IL-6-regulating transcription factors were quantitated.
Peripheral pSS monocytes produced significantly higher amounts of sBAFF and IL-6 than normal monocytes did, even in the absence of stimulation. The production of these cytokines was significantly increased upon stimulation with IFN-γ. The elevated production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of pSS monocytes with sBAFF induced a significant increase in IL-6 production. Moreover, the expression levels of a BAFF receptor and transcription factors regulating IL-6 were significantly elevated in pSS monocytes compared to normal monocytes.
The results of the present study suggest that the mechanisms underlying the production of sBAFF and IL-6 are impaired in pSS monocytes. Our research implies that this impairment is due to abnormally overexpressed IL-6-regulating transcription factors and a BAFF receptor. These abnormalities may cause the development of pSS.
Sjögren's syndrome (SS) is an autoimmune disease which primarily affects the salivary and lachrymal glands. Major clinical manifestations of primary SS (pSS) are xerostomia and keratoconjunctive sicca, which are consequences of lesions of the salivary glands and lachrymal glands, respectively. Accumulating evidence suggests that lymphocytic infiltrate of exocrine glands plays a key role in lesion formation and the subsequent dysfunction of the glands .
B-cell-activating factor of the TNF family (BAFF) (tumor necrosis factor ligand superfamily, member 13b) is a cytokine which is primarily produced by monocytes and dendritic cells [2–4] in addition to T cells [5, 6]. It plays a crucial role in the proliferation, differentiation and survival of B cells [2, 4, 5, 7]. BAFF is a type II membrane-bound protein of 285 amino acid residues. A C-terminal fragment of 152 amino acid residues is released from cells as soluble BAFF (sBAFF) . sBAFF binds to its receptors (that is, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B cell maturation antigen (BCMA) and B cell activating factor receptor (BAFF-R) [8–14]), possibly as a trimer [8, 11, 13], and elicits signal transduction through several pathways [10, 11, 13, 15, 16]. It is noteworthy that transgenic mice that overexpress BAFF in lymphoid cells develop hyperplasia of mature B cells [8, 17, 18] or pSS-like pathology . BAFF is also elevated in the serum of pSS patients [20, 21] and strongly expressed in the lymphocytes infiltrating the salivary glands [22, 23]. Moreover, elevated production of BAFF has been linked to the development of another autoimmune disease, systemic lupus erythematosus [24–26].
Notably, systemic and/or local concentrations of several other cytokines, such as IL-6, are also significantly elevated in pSS patients compared to normal individuals [27, 28]. IL-6 promotes the differentiation of B cells , which play a pivotal role in the production of autoantibodies and hence in the development of pSS. Since monocytes produce both IL-6  and BAFF [2, 4, 31], we hypothesized that the production of these cytokines is dysregulated in pSS monocytes. If that is the case, aberrations of pSS monocytes may be implicated in the abnormal production of autoreactive immunoglobulin G (IgG) by B cells, which is involved in the pathogenesis of autoimmune diseases such as pSS . In the present study, we demonstrate that the regulatory mechanisms for the production of these cytokines are impaired in pSS monocytes.
Materials and methods
Patients and controls
Venous blood samples were collected from pSS patients (n = 13 females ages 32 to 64 years (average age = 50.5)) and normal individuals (n = 12 females ages 26 to 60 years (average age = 43.5)) after receiving their informed consent. Patients fulfilled the American-European Consensus Group criteria for pSS . At the time of the collection of blood samples, two patients (15.4%) were receiving prednisolone at a daily dose < 5 mg. The remaining patients were free of medication. This study was approved by the ethics committees at Keio University School of Medicine and Saitama Medical University.
Stimulation of peripheral monocytes in vitro
Peripheral monocytes were isolated as follows: Whole blood was mixed with RosetteSep Human Monocyte Enrichment Cocktail (StemCell Technologies, Vancouver, BC, Canada) and centrifuged over Ficoll-Hypaque (Beckman Coulter, Fullerton, CA, USA). A monocyte-enriched fraction was collected and cultured overnight in RPMI 1640 (American Tissue Culture Collection, Manassas, VA, USA) supplemented with 10% FCS in a humidified incubator (7% CO2) at 37°C so that the expression of various stress-induced genes subsided. The cells were then washed once with the medium to remove debris. Fluorescence-activated cell sorting (FACS) analysis of the cells demonstrated that > 96% of the living cells were CD14-positive.
The monocytes were cultured in the absence or presence of various concentrations of IFN-γ or sBAFF, and the cumulative production of sBAFF and/or IL-6 was examined by ELISA. The production was dependent on the incubation period. The optimal incubation period was found to be 96 hours. The production of the cytokines increased almost in proportion to the concentration of stimuli up to 200 ng/ml IFN-γ or 2 μg/ml sBAFF.
Antibodies and recombinant proteins
An anti-BAFF mAb for ELISA was prepared in our laboratory . A rabbit polyclonal anti-BAFF antibody and recombinant human sBAFF were purchased from Chemicon International (Temecula, CA, USA). Recombinant human IFN-γ, a control mouse IgG1, and mAbs for measurement of the amount of IL-6 by ELISA (MQ2-13A5 and MQ2-39C3 for capture and detection, respectively) and for FACS analysis (CD4-APC (RPA-T4) for T cells, CD14-PE-Cy7 (M5E2) for monocytes, CD20-APC-Cy7 (L27) for B cells and CD268-FITC (11C1) for BAFF-R) were purchased from BD Biosciences/Pharmingen (San Diego, CA, USA). An anti-TACI antibody for FACS analysis (CD267-PE (FAB1741P)) was purchased from R&D Systems (Minneapolis, MN, USA).
Monocytes were cultured at 2.5 × 105/ml for 96 hours in a 24-well plate (2 ml/well) in the presence of stimuli (that is, recombinant human IFN-γ or recombinant human sBAFF). The amounts of sBAFF (in response to IFN-γ as a stimulus) and IL-6 (in response to IFN-γ or sBAFF as stimuli) in the culture supernatants were measured by sandwich ELISA according to previously described methods , except for the concentrations of capture and detection antibodies for IL-6, which were prepared at 0.5 μg/ml.
For quantitation of sBAFF, we used our own anti-BAFF mAb, which specifically detects sBAFF and does not react with a proliferation-inducing ligand (APRIL) . In our hands, the sensitivity of our ELISA system was better than that of commercially available ELISA kits (R&D Systems) in the range of 0.4 to 100 ng/ml sBAFF (data not shown).
Quantitation of the gene expression levels
The expression levels of BAFF, BAFF-R, TACI, NF-IL6, NF-IL6β, NF-κB1, NF-κB2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were quantitated by using a method described previously . The following oligonucleotides were used as primers for PCR: 5'-ggaatctctgatgccacagctc and 5'-accttcaagggctgtcaaagatg (BAFF-R); 5'-agcatcctgagtaatgagtggcc and 5'-gagcttgttctcacagaagtatgc (TACI); 5'-aaaactttggcactggggcacttg and 5'-catctttaagcgattactcagggc (NF-IL6); 5'-agatgcagcagaagttggtggag and 5'-tagcttctctcgcagtttagtgg (NF-IL6β); 5'-atgggatctgcactgtaactgc and 5'-tcatagatggcgtctgataccacg (NF-κB1); 5'-cctgactttgagggactgtatcca and 5'-gcagcatttagcagcaaggtcttc (NF-κB2). Primer sets for BAFF and GAPDH were designed as described previously . The expression level of each gene underwent dual normalization against GAPDH expression and expression of the same gene in unstimulated normal monocytes.
FACS and data analyses were carried out on a MACSQuant Analyzer (Miltenyi Biotec, Bergisch Gladbach, Germany). FACS analysis of cells in whole blood was carried out according to methods recommended by the manufacturer of the antibodies (BD Biosciences/Pharmingen).
Differences between groups were examined for statistical significance by using the two-tailed Student's t-test for single comparisons. Two-way analysis of variance (ANOVA) was also employed when appropriate. A P value less than 0.05 denoted the presence of a statistically significant difference.
Aberrant production of sBAFF by pSS monocytes
Clinical characteristics of primary Sjögren's syndrome patients involved in this study
Mean age ± SD (years)
50.5 ± 10.2
Subjective ocular dryness (%)
Subjective oral dryness (%)
Presence of anti-SSA/Ro (%)
Presence of anti-SSB/La (%)
Presence of rheumatoid factor (%)
Mean serum IgG ± SD (μg/ml)
1,979.6 ± 870.5
Steroid medication (%)
RT-PCR analysis indicated that the expression of the BAFF gene in pSS monocytes was distinctly elevated upon stimulation with IFN-γ (Figure 1B). Quantitative RT-PCR analysis indicated that the relative expression level of the BAFF gene was about three times higher in pSS monocytes than in normal monocytes under unstimulated conditions. The expression levels increased about sixfold in both normal and pSS monocytes upon stimulation with IFN-γ. These data are basically consistent with the results derived by ELISA. Therefore, we postulated that the elevated production of sBAFF was the consequence of the enhanced expression of the BAFF gene.
Aberrant production of IL-6 by pSS monocytes
A 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in a separate experiment indicated that 2 μg/ml sBAFF supported the survival of both normal and pSS monocytes during the culture period. However, there was no significant difference in survival rates between normal and pSS monocytes (data not shown), suggesting that higher production of IL-6 was not simply a consequence of enhanced survival of monocytes. These data suggest that the regulatory mechanism for IL-6 production is aberrant in pSS monocytes.
Aberrant expression of BAFF receptors in pSS monocytes
Expression of BAFF receptors in peripheral monocytes
100.0 ± 17.6
121.7 ± 20.4
100.0 ± 5.9
213.8 ± 14.9***
FACS analysis of lymphocytes in whole blood indicated that there were no significant differences between pSS patients and normal individuals in the population of BAFF-R-positive B and T cells (Figures 4C and 4D). All these data suggest that the expression of BAFF-R is dysregulated in pSS monocytes and that this dysregulation seems to be specific to monocytes among the cells examined thus far.
Aberrant expression of transcription factors in pSS monocytes
Expression of transcription factors in peripheral monocytes
100.0 ± 16.0
623.6 ± 85.8***
100.0 ± 18.5
252.8 ± 51.5*
100.0 ± 11.4
167.5 ± 23.4*
100.0 ± 14.9
342.6 ± 45.4***
Several lines of circumstantial evidence have suggested that BAFF and IL-6 are implicated in the development of primary pSS [19–23, 27, 28, 38]. In addition, these cytokines are produced by monocytes [2, 4, 39, 40]. These findings prompted us to investigate the possibility of aberrations in the monocytes of pSS patients. We hypothesized that the production of these cytokines is dysregulated in pSS monocytes. To address this issue, we examined the production of these cytokines by peripheral pSS monocytes in vitro in response to IFN-γ, a cytokine known to upregulate BAFF expression [2, 41]. As expected, pSS monocytes produced a higher amount of sBAFF than normal monocytes, even in the absence of stimulation (Figure 1A).
IFN-γ also induced the production of IL-6 by pSS monocytes. Interestingly, the induction was suppressed in part, but significantly, by an anti-BAFF antibody (Figure 2). In addition, exogenously supplemented sBAFF induced a striking increase in the production of IL-6 by pSS monocytes (Figure 3), whereas exogenously supplemented IL-6 had no effects on the production of sBAFF by the cells (data not shown). These data, together with the results shown in Figure 1A, collectively imply that BAFF produced by monocytes act in an autocrine fashion and that signal transduction pathways mediated by BAFF are likely involved in the regulation of IL-6 production by monocytes. Notably, two-way ANOVA indicated that pSS monocytes were more susceptible than normal monocytes to stimulation by sBAFF. This increased susceptibility may be due to an exaggeration of signals in pSS monocytes triggered by sBAFF.
BAFF is known to bind to several receptors, such as TACI, BAFF-R and BCMA [8, 10, 11, 13]. BAFF binds TACI  and BAFF-R [43, 44] with high affinity, whereas the binding affinity of BAFF to BCMA is very low [44, 45]. We found that a relatively small population of normal monocytes was TACI-positive (Figure 4B) and that the expression level of TACI did not increase in pSS patients (Table 2). Interestingly, expression of BAFF-R, a BAFF-specific receptor, was significantly elevated in pSS monocytes compared to the control (Table 2). FACS analysis suggested that this elevation may be the consequence of an increase not only in the population of BAFF-R-positive cells but also in the expression of the BAFF-R gene in individual pSS monocytes (Figure 4A). Considering all of this information together, we believe that abnormally overexpressed BAFF-R may have contributed to the enhanced production of IL-6 by pSS monocytes upon stimulation with sBAFF (Figure 3). The increase in the population of BAFF-R-positive cells was specific to pSS monocytes among the cells examined thus far, and no significant differences were observed in the population of BAFF-R-positive lymphocytes between pSS and the normal control (Figures 4C and 4D).
To shed light on the aberrant production of IL-6 by pSS monocytes, we examined the expression levels of several transcription factors involved in the expression of IL-6. Interestingly, the expression levels of all the transcription factors examined in the present study were significantly elevated compared to normal monocytes (Table 3). The expression of these transcription factors was generally constitutive and insensitive to stimulation, in particular with regard to sBAFF (data not shown). The expression level of NF-IL6 was especially high among the transcription factors examined. The higher expression of these factors may have amplified a signal triggered by sBAFF which resulted in overproduction of IL-6 by pSS monocytes. On the basis of the results shown in Figure 2 andTable 3 we suppose that IFN-γ induces the production of IL-6 in pSS monocytes through at least two distinct pathways: one is direct activation of the IL-6 gene and the other is indirect activation of the gene mediated by sBAFF.
The relationship between the aberration of pSS monocytes and the clinical manifestations of the disease remains unclear. There was no significant correlation between the presence of rheumatoid factor, anti-SSA/Ro or anti-SSB/La in pSS patients and the amounts of IL-6 and sBAFF produced by pSS monocytes. However, dendritic cells have been observed in the salivary glands of pSS patients [46–48], and peripheral monocytes can migrate to the salivary glands and develop into dendritic cells [49–51]. In addition, the local concentration of IFN-γ in the salivary glands of pSS patients seems to be increased because of T cells' infiltrating the tissue [51, 52]. Therefore, we hypothesize that monocyte-derived dendritic cells infiltrating the salivary glands of pSS patients are stimulated by IFN-γ to produce excessive amounts of BAFF and IL-6.
Although the number of the patients involved in the current study was small, the data strongly suggest that monocytes of pSS patients are abnormally activated. We hypothesize that stimulation of pSS monocytes by IFN-γ is partly mediated by BAFF as a result of the abnormal overexpression of BAFF-R and that the signals are amplified by abnormal overexpression of transcription factors that regulate IL-6 production. We speculate that these aberrations may underlie the pathogenesis of pSS.
analysis of variance
enzyme-linked immunosorbent assay
fetal calf serum
mean fluorescence intensity
polymerase chain reaction
primary Sjögren's syndrome
tumor necrosis factor.
We thank Dr Makoto Yoshimoto for his help in the preparation of this manuscript. This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (20591193).
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