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Scand J Rheumatol 2005;34:426432

Localization of human glucocorticoid receptor in rheumatoid synovial tissue of the knee joint
CT Tohyama1, M Yamakawa2, A Murasawa1, K Nakazono1, H Ishikawa1
Department of Orthopaedic Surgery, Rheumatic Centre, Niigata Prefectural Senami Hospital, Niigata, and 2Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
1

Objective: This study was conducted to investigate the localization of human glucocorticoid receptors (GCRs) in the knee synovium of patients with rheumatoid arthritis (RA) and to evaluate the correlation between GCR expression and the clinical profiles. Methods: Twenty synovial specimens from RA knees, six from knees with osteoarthritis (OA), and five from knees with traumatic arthritis (TA) were obtained at surgery. The GCRs were stained immunohistochemically. The immunopositive cells were counted at random in the lining (synoviocytes) and sublining layers (fibroblastic and lymphoid cells). The relationship between the GCR-expressing cells and clinical profiles was analysed statistically. Results: GCRs were expressed in the nuclei of synoviocytes and the fibroblastic and lymphoid cells in the sublining layer. The GCR-positivity rate of synoviocytes was 67.118.4% in RA, 58.713.5% in OA, and 49.419.7% in TA, differences between the three groups being statistically insignificant. There was a significant difference in the GCR-positivity rate of sublining fibroblastic cells (p50.029), but not synoviocytes or sublining lymphoid cells, from RA patients treated with and without prednisolone, while there was no correlation between the rate for synoviocytes and that for sublining fibroblastic cells from RA patients treated with prednisolone. Conclusions: GCRs are localized not only on inflammatory lymphoid cells but also on synoviocytes, suggesting that glucocorticoids could act directly on these cells. Furthermore, the rate of GCR expression on synoviocytes and sublining lymphoid cells is less suppressed with low-dose prednisolone, regardless of the duration of treatment.

For many years, glucocorticoids, such as prednisolone and cortisol, have been used widely for the treatment of rheumatoid arthritis (RA) because of their anti-inflammatory and immunosuppressive effects (13). Although some of the mechanisms of action of glucocorticoids have been elucidated, many questions remain (2, 3). In general, glucocorticoids bind initially to the glucocorticoid receptors (GCRs) in the plasma membrane, and then the GCRligand complex is transferred to in the nucleus for various genomic actions (4). Almost all nucleated cells in humans have GCRs, but glucocorticoids act primarily at sites of inflammation and where the immune response has been activated (2, 3). In RA patients, GCR activity has been examined mainly in peripheral mononuclear lymphocytes, using a binding assay (58). In the main
C. T. Tohyama, 2-5-13 Minami-machi, Murakami 958-0852, Niigata, Japan. E-mail: xkffg160@yahoo.co.jp Received 21 November 2004 Accepted 13 May 2005

it has been reported that the expression of GCRs is downregulated in RA. It is rare to encounter clinical cases where the steroid effect has been reduced after long-term glucocorticoid treatment, although the effect is not the same in each patient due to individual differences. Joint synovial tissue is ideal for the study of the pathogenesis of RA, and in particular the examination of GCR activity, because the main site of inflammation in this condition is the synovial tissue itself. To our knowledge, there is little information available on the immunohistochemical expression of GCRs in rheumatoid synovial tissue (9, 10). We therefore investigated immunohistochemically the expression of GCRs in RA synovium on knee joints to evaluate the correlation between GCR expression and the patients clinical background. Materials and methods Materials Twenty synovial specimens from 16 RA patients, six from five patients with osteoarthritis (OA),

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DOI: 10.1080/03009740510026850

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and five from five patients with traumatic arthritis (TA; controls) were obtained at surgery total knee arthroplasty or arthroscopic surgery at the Senami RA centre between 1999 and 2000. The clinical profiles of the patients are summarized in Table 1. The mean age was 61.7 years (range 3273 years) for the RA patients, 70.7 years (range 6379 years) for the OA patients, and 56.5 years (range 5156 years) for the TA patients. The mean disease duration was 16 years (range 135 years) for the RA patients. Of the 16 RA patients, 12 had been taking prednisolone at doses ranging from 2.5 to 7.5 mg/day (mean 4.7 mg/day) for 0.111 years (mean 4.3 years). Some of the RA patients were taking diseasemodifying anti-rheumatic drugs (DMARDs): four were taking methotrexate, two were taking either bucillamine or D-penicillamine, and one was taking cyclophosphamide. The preoperative rheumatoid factor (RF) was positive in 15 of the 16 RA patients and the C-reactive protein (CRP) level ranged from 0.1 to 18 mg/dl (mean 6.2 mg/dl). Methods The synovial tissue specimens were fixed with 10% formalin immediately after surgery, cut into 5-mmthick slices, and embedded in paraffin wax. Fourmicrometre-thick paraffin sections were cut from
Table 1. Clinical profiles of rheumatoid arthritis patients. Case no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Age (years) 64 67 71 73 58 55 50 67 68 67 52 32 57 71 71 66 Sex Female Female Female Male Female Female Female Female Female Male Female Female Female Female Female Male Duration of disease (years) 20 16 18 1 1 33 10 10 31 31 11 11 35 5 26 7 16 8 3 31 Operation procedure TKA TKA TKA Arthroscopic Arthroscopic TKA TKA TKA TKA TKA TKA TKA TKA TKA TKA Arthroscopic TKA Arthroscopic TKA TKA

these blocks and used for GCR immunostaining. The GCR was detected by incubation of the sections with a monoclonal mouse anti-human GCR antibody (4H2, mouse IgG2a, YLEM, Rome, Italy), and then visualized using the labelled streptavidinbiotin peroxidase complex method with the DAKO LSAB2 system (DAKO, Carpinteria, CA, USA) (11). The chromogen (in this case horseradish peroxidase) was visualized with 3,39-diaminobenzidine (Dojin, Kumamoto, Japan). The immunostained sections were counterstained with haematoxylin. A monoclonal antibody against GCR (4H2) recognized both GCR-a and GCR-b. The rate of positive cells in both the lining layer (synoviocytes) and the sublining layer (fibroblastic and lymphoid cells) was counted at random in every sample by two independent examiners (CT and MY) who had no knowledge of the clinical background of each sample. Statistical analysis The relationship between the rate of GCR-positive cells and clinical data including age, disease duration, history of prednisolone treatment, preoperative RF, and preoperative CRP was analysed statistically with the Spearmann test or the MannWhitney U-test. Significance levels were set at pv0.05, and all statistical analyses were carried out using Statview for Macintosh.

Preoperative RF (IU/mL) 64 146 75 547 547 569 163 163 30 30 18 18 81 85 1,952 112 102 63 161 865

Preoperative CRP (mg/mL) 7.6 8.2 1.3 18 18 1.9 8.5 8.5 3.1 3.1 6.2 6.2 0.1 6.8 5.1 5.9 10.2 3.9 0.2 1.5

DMARDs DPC BCL 1T MTX 3 CY CY ACT 3 ACT 3 AF 2T AF 2T DPC MTX 2 GST MTX 2+DPC BCL 2 MTX 2 BCL 1

PSL Duration of PSL (mg/day) treatment (years) 5.0 0 7.5 2.5 2.5 2.0 2.5 2.5 2.5 2.5 5.0 5.0 0 5.0 7.5 0 5.0 5.0 5.0 0 9 0 4 0.5 0.5 1 5 5 5 5 v1 v1 0 0.8 11 0 5 v1 1.5 0

RF. rheumatoid factor; CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; PSL, prednisolone; TKA, total knee arthroplasty; DPC, D-penicillamine; BCL, bucillamine; MTX, methotrexate; CY, cyclophosphamide; ACT, actarid; AF, auranofin; GST, gold sodium thiomalate.

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There was no significant difference in the rate of GCRexpressing synoviocytes and sublining lymphoid cells between RA cases with and without prednisolone treatment (Figure 4, 6).

Figure 1. Comparison of the frequency of glucocorticoid receptor (GCR)-positive synoviocytes among rheumatoid arthritis, osteoarthritis, and traumatic arthritis.

Results GCRs were expressed on the nuclei of cells in all of the samples. The mean percentage (standard deviation) of GCR-positive lining synoviocytes per randomly counted synoviocytes was 67.118.4% in the RA group, 58.713.5% in the OA group, and 49.419.7% in the TA group (Figure 1). Although many cases of the group exhibited high percentages of GCR-positive cells, there was no significant difference among the three groups (RA vs. OA: p50.287, RA vs. TA: p50.118, OA vs. TA: p50.584 by the MannWhitney U-test). GCRs were detected predominantly on the inflammatory lymphoid cells in the sublining layer (Figure 2A, B). The fibroblastic cells in the sublining layer were occasionally GCRpositive (789%; Figure 2B) in all RA cases. Compared with the OA and TA patients (Figure 3), most of the RA patients had a high percentage of GCR-positive cells in this layer, although again the differences were not significant among the three groups (RA vs. OA: p50.394, RA vs. TA: p50.154, OA vs. TA: p50.361 by the MannWhitney U-test). In the sublining layer, GCRs were detected in the majority of lymphoid cells. The other cell types of the sublining cells, such as vascular endothelial cells and smooth muscle cells, and macrophages were also positive for GCRs. Evaluation of intraobserver reproducibility revealed no statistically significant difference, and a strong correlation was found between the two observers. In the RA patients who had been taking the low doses of prednisolone, the rate of GCR-positive fibroblastic cells per randomly counted sublining fibroblastic cells was significantly higher than in those who had not received prednisolone treatment (Figure 5, p50.029).
B

Figure 2. Immunostaining of glucocorticoid receptors (GCRs) in synovial tissue obtained from a female patient (67 years old) with rheumatoid arthritis (RA). (A, B) Most of the massively infiltrating lymphoid cells in the sublining layer express GCRs. Note the frequent positive reaction on synoviocytes, located between the arrows. (C) Occasional fibroblastic cells (arrows) in the sublining layer express GCRs. This section was counterstained with haematoxylin. Original magnification (A, B) 6200.

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Figure 3. Immunostaining of GCRs in synovial tissue obtained from a male patient (51 years old) with traumatic arthritis (A) and from a female patient (71 years old) with osteoarthritis (B). Vascular endothelial cells and smooth muscle cells are evidently positive. Note the GCR expression on lining synoviocytes even in non-RA synovial tissues. This section was counterstained with haematoxylin. Original magnification (A, B) 6200.

Finally, the correlation between the rate of GCRpositive cells and other clinical characteristics of RA cells and other clinical patients including their cells and other clinical age, duration of the disease, duration of prednisolone treatment, and preoperative RF and CRP levels was examined (Table 2). The level of RF correlated well, but not significantly, with the rate of GCR-positive synoviocytes (r50.473, p50.064) and sublining lymphoid cells (r50.036, p50.084). The preoperative CRP level was significantly correlated with the rate of GCR-positive sublining lymphoid cells (r50.414, p50.046).

Discussion A reduction in GCR activity has been demonstrated in a variety of cells in RA synovial tissues after corticosteroid treatment, and this is one of the candidate causes of steroid resistance in therapy (12 18). In most of these studies a binding assay with 3Hdexamethasone was applied to evaluate GCR activity quantitatively (68, 15). The present study is the first to examine quantitatively the immunohistochemical expression of GCR on cells in synovial tissues taken from patients with active RA.

Figure 4. Comparison of the frequency of glucocorticoid receptor (GCR)-positive synoviocytes between RA groups treated with and without prednisolone.

Figure 5. Comparison of the frequency of glucocorticoid receptor (GCR)-positive sublining fibroblastic cells between RA groups treated with and without prednisolone.

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Figure 6. Comparison of the frequency of glucocorticoid receptor (GCR)-positive sublining lymphoid cells between RA groups treated with and without prednisolone.

It is well known that almost all nucleated cells in humans have GCRs (2, 3), and that GCR activity is found mainly in lymphoid cells (58). In the study presented here, GCRs were indeed found on many types of cell, such as lymphoid cells, fibroblastic cells, endothelial cells, and smooth muscle cells in the sublining layer. In addition, we found that most of the lining synoviocytes expressed GCRs (67.118.4% in the RA group, 58.713.5% in the OA group, and 49.419.7% in the TA group), suggesting that glucocorticoids directly target synoviocytes. As glucocorticoids can induce a G1 cellcycle arrest and programmed cell death, they exert an antiproliferative response in different cell types, including fibroblasts (10). The previous reports also support the possibility of glucocorticoids acting directly on synoviocytes (19, 20).

Several studies have recently reported GCR isoforms, such as a, b, and c, and also mutations and/or polymorphisms of the GCR gene (2126). In particular, GCR-b function was reported as a dominant-negative inhibitor GCR-a. However, conflicting data have also been reported (27). One paper states that the ratio GCR-b/GCR-a is very low (1/104) (28), although there might be some difference between the tissues and cells (29). We have indeed experienced steroid-resistant RA cases clinically, but only a very few such cases. Additionally, the previous reports were mostly based on the molecular level, while more factors might have affected each other in vitro. Therefore, our data showed general GCR localization in synovium clinically with some variation for each patient, which is the same pattern as OA and traumatic cases. Although the GCRs were detected on the lining synoviocytes and sublining fibroblastic and lymphoid cells, regardless of prednisolone administration, the rate of GCR expression on subsynovial fibroblastic cells in RA cases pretreated with prednisolone was significantly lower than in those who had not received prednisolone treatment. In our cases the maximum glucocorticoid dose was 7.5 mg/day, and our data have demonstrated that a low-dose glucocorticoid treatment (30) does not downregulate GCR expression on synoviocytes and extensively infiltrating lymphoid cells, even after long-term usage. This concurs with the finding of previous reports that lowdose steroid treatment may not suppress GCR activity (16, 31). Our data provide clinical support for the fact that GCR activity at the onset of RA without steroid therapy could be higher, because higher GCR activity was detected in most RA cases regardless of whether there were other factors present that could suppress GCR activity in the lengthy duration of the disease (32).

Table 2. Correlation between the rate of glucocorticoid receptor-positive cells and clinical profiles of rheumatoid arthritis patients. Sublining layer Clinical profiles Age Duration of disease Duration of prednisolone treatment Rheumatoid factor C-reactive protein r p r p r p r p r p Synoviocytes 0.103 0.403 0.108 0.794 0.093 0.808 0.473 0.064 0.154 0.699 Fibroblastic cells 0.119 0.748 0.072 0.430 0.379 0.139 0.503 0.338 0.205 0.691 Lymphoid cells 0.103 0.938 0.239 0.447 0.039 0.694 0.036 0.084 0.414 0.046*

r5correlation coefficient, p5p-value. *pv0.05.

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9. Handel ML, McMorrow LB, Gravallese EM. Nuclear factorkB in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum 1995;38:176270. 10. Theocharis S, Kouraklis G, Margeli A, Agopitos E, Ninos S, Karatza G, et al. Glucocorticoid receptor (GR) immunohistochemical expression is correlated with cell cycle-related molecules in human colon cancer. Dig Dis Sci 2003; 49:174550. 11. Handa K, Yamakawa M, Takeda H, Kimura S, Takahashi T. Expression of cell cycle markers in colorectal carcinoma: superiority of cyclin A as an indicator of poor prognosis. Int J Cancer 1999;84:22533. 12. Eggert M, Kluter A, Rusch D, Schmidt KL, Dotzlow H, Schulz M, et al. Expression analysis of the glucocorticoid receptor and the nuclear factor-kB subunit p50 in lymphocytes from patients with rheumatoid arthritis. J Rheumatol 2002;29:25006. 13. Cutolo M, Accardo S, Villagio B, Barone A, Sulli A, Coviello DA, et al. Androgen and estrogen receptors are present in primary cultures of human synovial macrophages. J Clin Endocrinol Metab 1996;81:8207. 14. Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative b isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA 2001;98:686570. 15. Neeck G, Kluter A, Dotzlaw H, Eggert M. Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis. Ann N Y Acad Sci 2002;966:4915. 16. Huisman AM, Siewertsz van Everdingen AA, Wenting MJ, Lafeber F, van Reesema, et al. Glucocorticoid receptor upregulation in early rheumatoid arthritis treated with low dose prednisone or placebo. Clin Exp Rheumatol 2003;21: 21720. 17. van Everdingen AA, Huisman AM, Wenting MJ, Lafeber FP, van Reesema DR, Jacobs JW, et al. Down regulation of glucocorticoid receptors in early-diagnosed rheumatoid arthritis. Clin Exp Rheumatol 2002;20:4638. 18. Huisman AM, Van Everdingen AA, Wenting MJ, Siewertsz Van Reesema DR, Lafeber FP, et al. Glucocorticoid receptor downregulation in early diagnosed rheumatoid arthritis. Ann N Y Acad Sci 2002;966:647. 19. Pelletier JP, Di Battista JA, Zhang M, Fernandes J, Alaaeddine N, Martel-Pelletier J. Effect of nimesulide on glucocorticoid receptor activity in human synovial fibroblast. Rheumatology (Oxford) 1999;38 Suppl 1:1113. 20. Cuchacovich M, Tchernitchin MN, Gatica H, Wurgraft R, Contreras L, Tchernitchin AN. Patients with rheumatoid arthritis: study of the correlation between density of glucocorticoid receptors in synovial cells and clinical response to steroidal treatment. Rev Med Chil 1996;124:1609. 21. Koga Y, Matsuzaki A, Suminoe A, Hattori H, Kanemitsu S, Hara T. Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2005;45:1217. 22. Charmandari E, Chrousos GP, Ichijo T, Bhattacharyya N, Vottero A, Souvatzoglou E, et al. The human glucocorticoid receptor (hGR) beta isoform suppresses the transcriptional activity of hGRalpha by interfering with formation of active coactivator complexes. Mol Endocrinol 2005;19:5264. 23. Pederson KB, Geng CD, Vedeckis WV. Three mechanisms are involved in glucocorticoid receptor autoregulation in human T-lymphoblast cell line. Biochemistry 2004;31:108518. 24. Lu NZ, Cidlowski JA. The origin and functions of multiple human glucocorticoid receptor isoforms. Ann N Y Acad Sci 2004;1024:10223.

Preoperative CRP levels were significantly correlated with the rate of GCR-positive fibroblastic cells in the sublining layer. This supports the idea that an increased rate of GCR-positive fibroblastic cells may be related to the pathogenesis of RA, as has been reported previously (15, 31). Some inflammatory stimuli may lead to the induction of proinflammatory cytokines such as tumour necrosis factor-a and interleukins-1, -6, and -8 (33). These cytokines activate transcription nuclear factorkB (NF-kB), which can then enhance GCR expression in the cytoplasm and translocate into the nucleus (34). Furthermore, the induction of endogenous glucocorticoids by proinflammatory cytokines will activate GCRs in the nucleus, which can then repress NF-kB expression. These mechanisms lead to the anti-inflammatory effect of glucocorticoids (10, 12, 3537). Glucocorticoids are known to play an important role in various physiological functions, not only by modulating inflammation but also by inhibiting, among other things, growth (37), and osteoporosis (1). The long-term administration of glucocorticoids also results in many adverse side-effects (1). Thus, improvements in the treatment of RA will be made if non-glucocorticoid compounds can be developed that activate GCRs or induce directly the expression of NF-kB (32, 38). We have demonstrated here the localization of GCRs not only on inflammatory lymphoid cells but also on synoviocytes, suggesting that corticosteroids could act directly on these cells. It was also revealed that the rate of GCR expression on synoviocytes and extensively infiltrating lymphoid cells was less suppressed with low-dose prednisolone treatment, despite long-term use. References
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