Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts:: a mechanism for tissue-specific regulation of inflammation
Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts:: a mechanism for tissue-specific regulation of inflammation
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DOI：
10.1186/ar1993
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发表时间：
2006-01-01
影响因子：
4.9
通讯作者：
Hewison, Martin
中科院分区：
文献类型：
--
作者：
Hardy, Rowan S.;Filer, Andrew;Hewison, Martin
基质细胞，如成纤维细胞，在炎症消退过程中，在确定组织特异性反应方面发挥着重要作用。我们假设这涉及糖皮质激素的组织特异性调节，通过对酶11β-羟基类固醇脱氢酶1(11β-HSD1)的不同调节。11β-HSD1在来自类风湿关节炎或骨关节炎患者不同组织(滑膜、骨髓和皮肤)的配对成纤维细胞中的表达、活性和功能进行了评估。11β-HSD1在所有组织的成纤维细胞中都有表达，但滑膜成纤维细胞的mRNA水平和酶活性更高(真皮和滑膜成纤维细胞的mRNA水平分别是骨髓的2倍和13倍)。经肿瘤坏死因子-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：分别是赋形剂的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；均为赋形剂的0.01倍)。IL-4或干扰素-γ治疗无效，从类风湿性关节炎或骨关节炎患者获得的成纤维细胞(来自任何部位)之间11β-HSD1的表达没有差异。在100nmol/L的可的松存在下，滑膜成纤维细胞的IL-6产生显著减少，而真皮和骨髓成纤维细胞则没有。这是通过与11β-HSD抑制剂联合治疗来预防的，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的差异(通过酶11β-HSD1)可能在某些组织易发生持续性炎症的过程中发挥关键作用。
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 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Expression, activity and function of 11 beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11 beta-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-1 beta (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 11 beta-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 11 beta-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 11 beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.