Hardy Rowan S, Filer Andrew, Cooper Mark S, Parsonage Greg, Raza Karim, Hardie Debbie L, Rabbitt Elizabeth H, Stewart Paul M, Buckley Christopher D, Hewison Martin
Division of Medical Sciences, Institute of Biomedical Research, The University of Birmingham Medical School, Birmingham, UK.
Arthritis Res Ther. 2006;8(4):R108. doi: 10.1186/ar1993.
Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.
诸如成纤维细胞之类的基质细胞在炎症消退过程中确定组织特异性反应方面发挥着重要作用。我们推测这涉及糖皮质激素的组织特异性调节，其通过对1型11β - 羟基类固醇脱氢酶（11β - HSD1）的差异调节来介导。在从类风湿性关节炎或骨关节炎患者获得的各种组织（滑膜、骨髓和皮肤）中分离得到的配对成纤维细胞中评估了11β - HSD1的表达、活性和功能。11β - HSD1在所有组织的成纤维细胞中均有表达，但滑膜成纤维细胞中的mRNA水平和酶活性更高（相对于骨髓，真皮和成纤维细胞中的mRNA水平分别高2倍和13倍）。在用肿瘤坏死因子 - α或IL - 1β处理后，所有成纤维细胞中该酶的表达和活性均增加（骨髓：与载体相比分别增加8倍和37倍；真皮成纤维细胞：4倍和14倍；滑膜成纤维细胞：7倍和31倍；与载体相比所有P < 0.01）。用IL - 4或干扰素 - γ处理无效，并且类风湿性关节炎或骨关节炎患者的成纤维细胞（来自任何部位）之间11β - HSD1表达没有差异。在存在100 nmol/l可的松的情况下，滑膜衍生的成纤维细胞的特征性特征——IL - 6产生在滑膜成纤维细胞中显著降低，但在真皮或骨髓成纤维细胞中未降低。用11β - HSD抑制剂共同处理可防止这种情况，强调了滑膜成纤维细胞中糖皮质激素自分泌激活的可能性。这些数据表明，来自不同解剖位置的细胞之间成纤维细胞衍生的糖皮质激素产生（通过11β - HSD1酶）的差异可能在某些组织易发生持续性炎症中起关键作用。
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