Increased expression of CD14 in macrophages after inhibition of the cholesterol Biosynthetic pathway by lovastatin
Increased expression of CD14 in macrophages after inhibition of the cholesterol Biosynthetic pathway by lovastatin
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DOI：
10.2119/2007-00054.frey
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
De Maio, Antonio
中科院分区：
文献类型：
--
作者：
Frey, Tiffany;De Maio, Antonio
脓毒症是炎症反应控制不良的产物，是一个主要的健康问题。脓毒症尚无足够的治疗方法，患者护理主要是支持性的。他汀类药物广泛用于治疗高胆固醇血症，已被发现具有抗炎作用，但导致炎症反应改变的机制尚不清楚。我们研究了他汀类药物对 CD14 表达的影响，CD14 是巨噬细胞表面细菌脂多糖 (LPS) 的主要结合位点，CD14 以细胞表面的膜结合形式 (mCD14) 和循环中的可溶性变体 (sCD14) 形式存在。用洛伐他汀处理 RAW 264.7 巨噬细胞会导致 LPS 刺激后 mCD14 水平升高并降低 sCD14 水平。 mCD14 的增加依赖于香叶基香叶基焦磷酸 (GGPP) 的消耗和随后对 Rho GTPases 的抑制，而洛伐他汀对 sCD14 的影响与该途径无关。 mCD14 表达的增加与 LPS 反应的增强相关，至少在肿瘤坏死因子 (TNF)-α 分泌水平上如此。这些结果表明他汀类药物治疗可以调节巨噬细胞功能，这可能对炎症和脓毒症的结果产生影响。
Sepsis, which is the product of a poorly controlled inflammatory response, is a major health problem. Adequate therapies for sepsis are unavailable, and patient care is mainly supportive. Statins, widely used for the treatment of hypercholesterolemia, have been found to be anti-inflammatory, but the mechanisms responsible for this alteration in the inflammatory response are not well understood. We investigated the effect of statins on CD14 expression, the major binding site for bacterial lipopolysaccharide (LPS) on the macrophage surface, CD14 is found in both a membrane-bound form on the cell surface (mCD14) and in a soluble variant in circulation (sCD14). Treatment of RAW 264.7 macrophages with lovastatin resulted in elevated mCD14 levels and decreased sCD14 levels after LPS stimulation. The increase in mCD14 was dependent on depletion of geranylgeranyl pyrophosphate (GGPP) and subsequent inhibition of Rho GTPases, whereas the effect of lovastatin on sCD14 was independent of this pathway. The increase in mCD14 expression correlated with an enhanced response to LPS, at least at the level of tumor necrosis factor (TNF)-alpha secretion. These results suggest that statin treatment can modulate macrophage function, which may have an impact on inflammation and the outcome from sepsis.