Rheumatol Int (2013) 33:1031–1037 DOI 10.1007/s00296-012-2459-4
ORIGINAL ARTICLE
Soluble CD163 serum levels are elevated and correlated with IL-12 and CXCL10 in patients with long-standing rheumatoid arthritis Claudia Jude • Doru Dejica • Gabriel Samasca Loredana Balacescu • Ovidiu Balacescu
•
Received: 15 January 2012 / Accepted: 7 July 2012 / Published online: 22 August 2012 Ó Springer-Verlag 2012
Abstract CD163, a membrane glycoprotein restricted to monocyte–macrophage cell lineage, is released in the terminal phase of acute inflammation and during chronic inflammation, with anti-inflammatory and antiangiogenic role. The proteolytically detached ectodomain of CD163 is the soluble component sCD163. A few studies were performed regarding circulating sCD163 in human diseases. Only two were accomplished in patients with rheumatoid arthritis (RA). Our concern was (1) to evaluate sCD163 serum concentrations in active RA patients with longstanding evolution, (2) to correlate them with clinical parameters, laboratory markers, disease activity, and (3) to search possible relationships with some cytokines (IL-12, IL-17) and chemokine (CXCL10), involved in RA pathogenesis. First and third topics were not achieved until now, and the second one points out discordant findings and unspecified aspects. It was achieved immunoassay of serum sCD163, IL-12, IL-17, CXCL10 and traditional methods for RA laboratory markers. The mean sCD163 level of 33 patients was significantly higher than in 20 normal controls (p = 0.0001), 59.3 % of them with concentrations above normal cut-off value. sCD163 levels were weakly correlated with CRP and RF but not with ERS and disease activity. IL-12 and CXCL10 serum levels
C. Jude D. Dejica (&) G. Samasca Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, Str.Plopilor No. 44, Cluj Napoca, Romania e-mail:
[email protected] L. Balacescu (&) O. Balacescu Department of Functional Genomics and Experimental Pathology, The Oncological Institute ‘‘Prof Dr. Ion Chiricuta’’, 34–36 Republicii Str, Cluj Napoca, Romania e-mail:
[email protected]
strongly correlated with sCD163 concentrations, while IL-17 positively but insignificantly correlated. In conclusion, serum sCD163 levels are significantly elevated in long-standing RA patients, but sCD163 has no role as a biomarker of disease activity. High correlation of sCD163 with IL-12 and CXCL10 suggests the association of their well-known anti-inflammatory function in long-standing RA patients. Keywords Rheumatoid arthritis Soluble CD163 IL-12 CXCL10
Introduction CD163 is a 130-kDa glycoprotein, exclusively expressed by the monocyte–macrophage cell lineage, identified in 1987, with a role in down-regulation phase of the inflammatory process [1, 2]. Ten years ago, CD163 was called ‘‘hemoglobin scavenger receptor’’, having the hemoglobin–haptoglobin (Hb–Hp) complex as ligand [3]. Thus, the oxidative stress induced by the heme (a Hb subunit) is removed and the inception of tissue lesions prevented [4]. Most tissue macrophages and at least 10–13 % of the circulating monocytes that generate them release increased CD163 amounts in the terminal phase of acute inflammation and during chronic inflammation [6–8]. They represent the phenotype of ‘‘alternatively activated macrophages’’ (M2), with anti-inflammatory, antioxidant, tissue repair, antiangiogenic, and fibrosing role, while macrophage activated by classical pathway (M1) has pro-inflammatory properties. The restrictive expression of CD163 by the monocyte–macrophage suggests that this molecule is a marker for its identification in various tissues. The differentiation of monocytes into tissue macrophage strongly
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induces CD163 mRNA, and consequently these cells express CD163. Some anti-inflammatory mediators, such as IL-10 and IL-4, intensely promote CD163 expression, while proinflammatory cytokines TNF a and IFN c suppress CD163 mRNA and subsequently the molecule expression [9–11]. On the other hand, the glucocorticoids have proved to be the first stimulants of CD163 expression by monocytes. Thus, in vitro treatment with glucocorticoids increases the percentage of CD163? cells from 10–30 % to 90 %, and dexamethasone injection enhances it to 80 % in 6 h [12]. The best characterized function of CD163, essentially homeostatic, is the coupling to the Hb–Hp complex. Intravascular hemolysis is accompanied by the release of Hb that binds to Hp, and CD163? macrophages scavenge Hb–Hp complex from plasma [6, 13]. After Hb–Hp endocytosis, the heme released is removed by constitutive heme oxygenase (HO-1), induced by anti-inflammatory stimulants such as IL-10 and IL-1 receptor antagonist, produced by activated monocytes and macrophages [14, 15]. CD163 mediates IL-10 release and HO-1 synthesis from/in these cells. In this turn, IL-10 enhances CD163 and HO-1 expression by a positive feedback, thus blocking hemedependent inflammatory tissue lesions. Due to the heme metabolites (CO, biliverdin, iron sequestered in ferritin), potent antioxidants, an anti-inflammatory effect is obtained [8]. On the other hand, under IL-10 and acute phase proteins (including Hp), decreased secretion of TNF a and IFN c is the outcome of ‘‘inflammatory macrophages inactivation [16, 17]’’. CD163 is a transmembrane molecule with endodomain and ectodomain. The proteolytically detached ectodomain is shed in blood stream, becoming the soluble CD163 component, sCD163 [18, 19]. A few studies have been performed regarding circulating sCD163 in human diseases. Elevated levels of sCD163 were demonstrated in patients with hemophagocytic syndrome, atherosclerosis, malignant hemopathies, celiac disease, and fulminant hepatic failure [5]. Rarely, serum/plasma sCD163 determination has been accomplished in patients with autoimmune rheumatic diseases like rheumatoid arthritis [20, 21], spondylarthropathy [22], and systemic sclerosis [23]. This study was achieved with the following aims: (1) to evaluate sCD163 serum levels in patients with long-standing evolution of rheumatoid arthritis in active disease; (2) to correlate the sCD163 serum concentrations with clinical manifestations, inflammatory/immunological markers, and with disease activity score; (3) to search possible relationships with some cytokines and a chemokine involved in rheumatoid arthritis pathogenesis, IL-12, IL-17, and CXCL 10, respectively. First and third topic are not until today investigated, and the second one contains discordant findings.
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Patients and methods Patients Thirty-three subjects with long-standing evolution of rheumatoid arthritis (mean 7.2, range 1–12 years) fulfilled the 1987 diagnosis and staging revised criteria, established by American College of Rheumatology [24], and were enrolled in the study. Consecutively hospitalized patients were recruited after written informed consent was obtained according to the Declaration of Helsinki and after approval of Ethic Committee of Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca. All patients had active disease, assessed by DAS 28: swollen and painful joints in at least 6 joints, morning stiffness [ 45 min, ESR [ 28 mm/h and CRP [ 1.5 mg %. The demographics, clinical and laboratory data of patients are detailed in the Table 1. Until blood samples were collected, 15 patients were treated with prednisone (10–15 mg/day), plus azathioprine, 9 received methotrexate (25 mg/week), 6 patients used leflunomide (Arava, 20–30 mg/day), and 3 patients used sulfasalasine (1.5–2 g daily). Certain patients received in the last weeks different associations of mentioned drugs and the majority of them added nonsteroidal anti-inflammatory drugs. Age- and sex-matched 20 volunteers blood donors (16 women, 4 men, aged 23–56 years), without a history of autoimmune, chronic inflammatory disease, and current ultrasound carotid intimal-medial thickness, suggestive for preclinical atherosclerosis, were recruited as normal controls. Immunoassays of serum sCD163, IL-12, IL-17, and CXCL10 Ten milliliter of peripheral venous blood was collected from patients and normal controls and stored at -70 °C for subsequent measurement by sandwich ELISA kits. For measurement of sCD163 concentration, we used Macro 163 TM kit (IQ Products, trillium Diagnostics, LLC, Groningen, Holland), with a detection level \ 0.23 ng/ml. Polyclonal CD163 antibodies are immobilized on the surface of the microtiter plate. After incubation with sample to be studied or standard recombinant CD163, biotinylated monoclonal antibodies were added to recognize CD163, further detected by addition of streptavidin peroxidase. Employing tetramethylbenzidine as substratum for HRP-streptavidin, sCD163 has been quantified. IL-12, IL-17, and CXCL10 serum levels were measured with kits provided by R&D Systems, Inc (Minneapolis, MN). Optical density was read at 450 nm during 30 min. Serum cytokines and chemokine concentrations were calculated with curves achieved by specific standards elaborated by manufacturer and results expressed in pg/ml. For IL-12,
Rheumatol Int (2013) 33:1031–1037 Table 1 Demographics, clinical and laboratory data of patients with rheumatoid arthritis
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Characteristics
RA total (n = 33)
Stage I (n = 7)
Stage II (n = 18)
Stage III (n = 8)
Female
29
6
16
17
Male
4
1
2
1
2 (21–30)
9 (31–40)
13 (41–50)
9 (51–60)
Mean
7
5
6
10
Range
1–12
1–9
3–10
3–12
Vasculitis (no.)
3
–
2
1
Sicca syndrome (no.)
3
–
2
1
12 13
9 9
11 14
13 16
Sex (no.)
Age (decade) Disease duration (years)
Organ involvement
Painful joints (mean) Swollen joints (mean) Laboratory findings CRP (mg %) (mean)
4.2
1.9
3.4
6.1
Rheumatoid factor (positive) no. (%)
20 (66.6)
5 (16.6)
13 (43.3)
2 (6)
ESR (mm/h) (mean) Disease activity (DAS28) (mean)
150
Statistical analysis
100
Data of measurements of serum sCD163, IL-12, IL-17, and CXCL10 were expressed as the mean ± standard deviation (SD). The difference between values of patients and controls were calculated with Mann–Whitney U test. Relationship between the 2 continuous variables was evaluated using Pearson’s correlation coefficient and Spearman’s rank correlation tests. The minimum level of significance was set at a ‘‘p’’ value of \ 0.05.
sCD163 (ng/ml)
capture antibodies were used, which only recognize human heteromer p70 but not the two subunits, p30 and p40. The minimum detectable amount was \5 pg/ml for IL-12, 15 pg/ml for IL-17, and between 0.14 and 4.46 pg/ml for CXCL10.
28.6
18.2
27.7
42.6
3.7
2.3
3.9
5.5
p = 0,0001
59,74
50 40,65
0
Results Serum sCD163 concentrations are shown in Fig. 1, representing individual values of patients and normal controls, their statistical mean, the cut-off (mean ? 2 SD of the control sera, broken line) and ‘‘p’’ significance of differences between those two groups of subjects. The levels of patients were comprised between 45.88 and 97.19 ng/ml, and the mean level of 59.36 ± 5.8 ng/ml was significantly higher than normal controls (p = 0.0001). Among RA patients, 59.3 % had serum sCD163 levels above cut-off normal value (54.03 ng/ml), estimated as increased/pathological concentrations.
normal controls ( n=20 )
rheumatoid arthritis ( n=33 )
Fig. 1 Mean serum level of sCD163 in long-standing rheumatoid arthritis patients was significant increased compared with normal controls (p = 0.0001). 59.3 % of patients have had higher concentrations than cut-off value of controls
Correlation of serum sCD163 with CRP, ESR, and rheumatoid factor (RF) sCD163 levels were positively and significantly correlated with CRP (r = 0.51 and p \ 0.01) and RF positivity (r = 0.48 and p \ 0.01) but not with ESR.
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Correlation of serum sCD163 with disease activity (DAS28) It was positive but without statistical significance. Correlation of serum sCD163 with clinical manifestations In order to assess a possible clinical signification of sCD163 modification in patients with long-standing rheumatoid arthritis, it was verified whether sCD163 levels are associated with the number of painful or swollen joints, morning joint stiffness duration, presence of some complications like vasculitis and sicca syndrome developed in our patients. No significant correlation was observed with any of these manifestations. Influence of therapy on serum sCD163 In our study, we did not find a significant difference of serum sCD163 levels depending on utilized drugs before enrolled moment in the study. Correlations of serum sCD163 with IL-12, IL-17, and CXCL10 The mean level of IL-12 was significantly higher in patients than in normal controls, and a high significant correlation between sCD163 and IL-12 concentrations was pointed out (r = 0.99 and p \ 0.0001) (Fig. 2). The mean sCD163 serum level of CXCL10 was significantly higher in patients compared with normal controls, and the concentrations of chemokine were high and significantly correlated with sCD163 (r = 0.994 and p = 0.0001)
Fig. 2 Correlation between serum IL-12 and sCD163 concentrations in long-standing rheumatoid arthritis patients was positively and high significantly (r = 0.98 and p \ 0.0001)
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Fig. 3 Correlation between serum CXCL10 an sCD163 concentrations in long-standing rheumatoid arthritis patients was positively and high significantly (r = 0.994 and p = 0.0001)
(Fig. 3). The mean level of serum IL-17 was significantly higher in patients compared with normal controls, and cytokine concentrations were positive but not significantly correlated with serum sCD163.
Discussion In the present study, it was determined the serum levels of sCD163 and their correlations with disease activity, clinical manifestations, traditional laboratory serology and IL-12, IL-17, CXCL10 in patients with long-standing rheumatoid arthritis, the last ones strong implicated molecule in early phase of disease. Our results are in accordance with elevated levels of serum sCD163 demonstrated for the first time 10 years ago [20], but the Japanese authors does not specify the duration of disease. Like the mentioned study, we neither found a significant correlation between serum sCD163 levels and disease activity, also expressed by DAS28, nor between sCD163 and clinical manifestations. The minimum significant correlation between sCD163 and CRP serum concentrations was in agreement with quoted paper. This versatile marker of rheumatoid arthritis reflects the systemic rather than the local activity of the rheumatoid inflammatory process. Unlike previous group, we studied the correlation between sCD163 concentration and the positivity of RF and it achieved no significant association. A recent investigation in 34 Danish early rheumatoid arthritis patients demonstrated significantly higher plasma level of sCD163 at baseline than after 9 months of treatment, but unexpected nonsignificantly changed compared with healthy volunteers [21]. The baseline levels of sCD163 correlated with DAS28, CRP, ESR and predicted
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radiographic progression, suggesting that sCD163 concentration may be a biomarker of disease activity and that resident macrophages are important for joint destruction. Regarding the influence of therapy on sCD163 levels in patients undergoing various drugs until blood collection, the difference was negligible in our study. It is well known that i.v. injection of high amounts of glucocorticoids (60 mg prednylidene) resulted in an increase in CD163? monocytes proportion to about 80 % after 12 h and after 24 h decreased but remained over the baseline level at least 15 days [25]. The statement that the higher sCD163 levels in our patients are due to prednisone can be questioned or doubtful. Thus, there is no certainty that the increase in CD163? monocytes proportion mentioned is accompanied by the release of a proportional amount of sCD163. On the other hand, if the presence of this correspondence is admitted, the dependence of high concentrations on the severity of the disease may be excluded since we did not find a significant correlation between sCD163 levels and disease activity, assessed by DAS28. The simultaneous measurement of serum and synovial fluid sCD163 with circulating and synovial tissue CD163? cells would elucidate this problem [26]. In the end, low doses of prednisone administered in our patients may support to the effect that serum sCD163 levels were not influenced by glucocorticoid therapy. High significant positive correlation of serum sCD163 levels with IL-12 and CXCL10 concentrations while it is missing with IL-17 was so far not pointed out, but arouses our interest concerning pathogenetic involvement of sCD163 in rheumatoid arthritis. It has recently been related that TACE/ADAM 17, the TNFa converting enzyme from classically activated macrophages (M1), concomitantly detaches the ectodomain of CD163, plasma levels being positively correlated with the severity of the inflammatory process [27]. In rheumatoid arthritis, the prevalent proinflammatory activity of cytokines TNFa, IL-1b, IL-12 p70, IL-17 is initiated, resulting in joint lesions, while in spondylarthritis and psoriatic arthritis, synovial activated lymphocytes (CD69 ?) are significantly decreased versus rheumatoid arthritis patients and CD163 ? macrophages more increased, what leads to inflammation suppression and the propensity to tissue repair [22, 28]. ‘‘Proarthritic’’ effect of IL-17 is already well proved, but IL-12 and CXCL10 play a dual, initial pro-inflammatory, and later protective role. A relevant aspect of ‘‘antiarthritic’’ activity of IL-12, subsequent its early pro-inflammatory effect in rheumatoid arthritis, has been experimentally demonstrated in the late phase of collagen type II arthritis [29], by inhibitory action on angiogenesis, mediated by CXCL10 [30, 31]. Moreover, IL-12 induces IL-10 production by T cells and the monocyte–macrophage cell lineage, IL-10 being a powerful stimulant of CD163 synthesis [11, 12]
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and a vigorous inhibitor of IFNc production [32]. Not at last, the anti-inflammatory activity of IL-12 is completed by the specific suppression of IL-17 production [33]. The strong correlation of serum sCD163 level with IL-12 concentration in patients with long-standing rheumatoid arthritis found by us suggests the coupling of the antiinflammatory effect of these molecules. Like IL-12, CXCL10 is a chemokine with destructive pro-inflammatory activity in early rheumatoid arthritis but a strong inhibitor of in vivo angiogenesis during the late phase of disease [34]. Recently, it was certified that the blockage of angiogenesis can lead to the suppression of synovial inflammation and of pannus enlargement [35]. The chemokine is powerfully induced by IFNc and IL-12. The last one stimulates IFN c production and sCD16 inhibits IFN c secretion. The result of these interactions is undoubtedly decided by proportion of one/some of these molecule to which other pro-inflammatory (e.g., IL-17) and antiinflammatory (e.g., IL-10) or other factors are added. The insignificant correlation between serum IL-17 and sCD163 shown in our patients with long-standing rheumatoid arthritis supposes opposite functions, IL-17 all the time with pro-inflammatory/destructive effect, while sCD163 has a ceaseless anti-inflammatory action. The increase in serum sCD163 level in patients with long-standing rheumatoid arthritis may be an indirect proof of the joint destructive aggression but does not a role as biomarker of disease activity, how is recently proposed in early rheumatoid arthritis [21]. What is the source of CD163 and how is detached sCD163 and released into synovial fluid and blood circulation of that extramembranal component of CD163? Macrophages are present in the cell infiltrate from rheumatoid synovium, and the number of CD163? macrophages is increased, significantly higher than in osteoarthritis synovium [36]. Activated metalloproteinase is considered to proteolytically cleave CD163, and sCD163 is detached from the macrophage surface and sheds in the synovial fluid that contains 10 times higher concentration than blood serum [20]. Besides synovial macrophages, sCD163 proceeds from circulating monocytes, plasma level being conversely correlated with CD163 expression by these cells [37]. What factors induce metalloproteinases activation involved in the CD163 cleavage off monocytes and macrophages surface? Lipopolysaccharide (LPS), a Gram-negative endotoxin, stimulates the excessive productions of many cytokines and acute phase proteins. The response to LPS is the rapid increase in the level of in vivo glucocorticoids and IL-10, important mediators of the CD163 synthesis [38]. At the same time, LPS activates monocytes by classical pathway, releasing great amounts of TNF a. The release of TNF a deprives monocytes and macrophages of CD163 by CD163 mRNA inhibition.
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After LPS administration to volunteers, monocyte CD163 expression is restored or become higher than before injection. This is due to the activity of toll-like cell receptors, as a result to the increase of circulating cortisol, IL-6 and IL-10 concentration, inducers of CD163 synthesis [12, 39]. Phorbol myristate acetate (PMA) yields the cleavage of CD163 [40]. This is one of the anti-inflammatory mechanisms performed by sCD163, through the reduction of immune response. In vitro, after LPS or PMA addition to the monocytes culture medium, previously treated with dexamethasone, more CD163 is delivered [38]. It was demonstrated that the interaction of sCD163 with activated T cells is mediated by the nonmuscular myosin heavy chain type A, very important intervention to diminish a chain of inflammatory process events [41]. Is essential to emphasize that only sCD163, not CD163, has a direct anti-inflammatory potential [42]. A natural mechanism of CD163 cleavage, with subsequent sCS163 release into synovial fluid and blood circulation, is the crossreaction of immune complexes with Fcc receptor [43]. The same effect is obtained by oxidative stress mediators from inflammatory process, produced by activated monocytes and TNFa [44]. Acknowledgments The authors would like to thank Prof. Dr. Martin Herrmann (Friederich Alexander University, Erlangen-Nurenberg, Germany) for helpful professional support, Prof. Dr. Simona Rednic (Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania) for kindly approval and Mrs. Ecaterina Piricsi for excellent secretarial contribution. Conflict of interest The authors declare that they have no conflict of interests and all equally contributed to this study.
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