11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the conversion of inactive cortisone into active cortisol, which has pleiotropic roles in various biological conditions, such as immunological and metabolic homeostasis. Cortisol is mainly produced in the adrenal gland, but can be locally regenerated in the liver, fat, and muscle. Its diverse actions are primarily mediated by binding to the glucocorticoid receptor. SW982, a human synovial cell line, expresses 11β-HSD type 1, but not type 2, that catalyzes the conversion of cortisone to cortisol. In this study, therefore, we investigated the control of lipopolysaccharide (LPS)-induced inflammatory responses by prereceptor regulation-mediated maintenance of cortisol levels. Preliminarily, cell seeding density and incubation period were optimized for analyzing the catalytic activity of SW982. Additionally, cellular 11β-HSD1 still remained active irrespective of monolayer or spheroid culture conditions. Inflammatory stimulants, such as interleukin (IL)-1β, tumor necrosis factor (TNF)α, and LPS, did not affect the catalytic activity of 11β-HSD1, although a high dose of LPS significantly decreased its activity. Additionally, autocrine effects of cortisol on inflammatory responses were investigated in LPS-stimulated SW982 cells. LPS upregulated pro-inflammatory cytokines, including IL-6 and IL-1β, in SW982 cells, while cortisol production, catalyzed by cellular 11β-HSD1, downregulated LPS-stimulated cytokines. Furthermore, suppression of NFκB activation-mediated pro-inflammatory responses by cortisol was revealed. In conclusion, the activity of cellular 11β-HSD1 was closely correlated with suppression of LPS-induced inflammation. Therefore, these results partly support the notion that prereceptor regulation of locally regenerated cortisol could be taken into consideration for treatment of inflammation-associated diseases, including arthritis.

中文翻译：

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细胞 11β-羟基类固醇脱氢酶 1 对滑膜细胞系中 LPS 诱导的炎症反应的影响，SW982

11β-羟基类固醇脱氢酶 1 (11β-HSD1) 催化无活性的可的松转化为活性的皮质醇，其在各种生物条件下具有多效作用，例如免疫和代谢稳态。皮质醇主要在肾上腺中产生，但可以在肝脏、脂肪和肌肉中局部再生。其多种作用主要通过与糖皮质激素受体结合介导。SW982 是一种人类滑膜细胞系，表达 11β-HSD 1 型，但不表达 2 型，可催化可的松转化为皮质醇。因此，在这项研究中，我们研究了通过前受体调节介导的皮质醇水平维持对脂多糖 (LPS) 诱导的炎症反应的控制。初步优化了细胞接种密度和孵育时间以分析SW982的催化活性。此外，无论单层或球体培养条件如何，细胞 11β-HSD1 仍保持活性。炎症刺激剂，如白细胞介素 (IL)-1β、肿瘤坏死因子 (TNF)α 和 LPS，不影响 11β-HSD1 的催化活性，尽管高剂量的 LPS 显着降低其活性。此外，在 LPS 刺激的 SW982 细胞中研究了皮质醇对炎症反应的自分泌作用。LPS 上调 SW982 细胞中的促炎细胞因子，包括 IL-6 和 IL-1β，而由细胞 11β-HSD1 催化的皮质醇产生下调 LPS 刺激的细胞因子。此外，还揭示了皮质醇对 NFκB 活化介导的促炎反应的抑制。总之，细胞 11β-HSD1 的活性与抑制 LPS 诱导的炎症密切相关。