Cho Young Sik, Kim Ki Nam, Shim Jung Hyun
Department of Pharmacy, Keimyung University, Daegu 42601, Korea.
Department of Pharmacy, College of Pharmacy, Mokpo National University, Mokpo 58554, Korea.
Immune Netw. 2017 Jun;17(3):171-178. doi: 10.4110/in.2017.17.3.171. Epub 2017 Jun 20.
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.
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皮质醇，皮质醇在多种生物学状态下具有多效性作用，如免疫和代谢稳态。皮质醇主要在肾上腺产生，但也可在肝脏、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是人滑膜细胞系，表达1型而非2型11β-HSD，可催化可的松转化为皮质醇。因此，在本研究中，我们通过受体前调节介导的皮质醇水平维持来研究脂多糖（LPS）诱导的炎症反应的调控。初步地，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，无论单层培养还是球体培养条件，细胞11β-HSD1均保持活性。炎症刺激物，如白细胞介素（IL）-1β、肿瘤坏死因子（TNF）α和LPS，均不影响11β-HSD1的催化活性，尽管高剂量LPS显著降低其活性。此外，还研究了皮质醇对LPS刺激的SW982细胞炎症反应的自分泌作用。LPS上调SW982细胞中包括IL-6和IL-1β在内的促炎细胞因子，而细胞11β-HSD1催化产生的皮质醇下调LPS刺激的细胞因子。此外，还揭示了皮质醇对NFκB激活介导的促炎反应的抑制作用。总之，细胞11β-HSD1的活性与LPS诱导的炎症抑制密切相关。因此，这些结果部分支持了这样一种观点，即对于包括关节炎在内的炎症相关疾病的治疗，可以考虑对局部再生皮质醇进行受体前调节。
