Division of Physiology Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Laboratory Medicine, Clinical Microbiology, Karolinska University Hospital, Huddinge, Stockholm, Sweden; and.
FASEB J. 2018 May;32(5):2827-2840. doi: 10.1096/fj.201701308. Epub 2018 Jan 17.
Prostaglandin (PG)E is an arachidonic acid-derived lipid mediator that plays an important role in inflammation and immunity. In this study, we demonstrate that PGE suppresses basal and 1,25-dihydroxy vitamin D (VD)-induced expression of hCAP18/LL-37 via E prostanoid (EP)2 and EP4 receptors. In humans, VD up-regulates vitamin D receptor (VDR) expression and promotes transcription of the cathelicidin hCAP18/LL-37 gene, whereas PGE counteracts this effect. We find that PGE induces the cAMP/PKA-signaling pathway and enhances the expression of the inhibitory transcription factor cAMP-responsive modulator/inducible cAMP early repressor, which prevents VDR expression and induction of hCAP18/LL-37 in human macrophages. The negative regulation by PGE was evident in M1- and M2-polarized human macrophages, although PGE displayed more profound inhibitory effects in M2 cells. PGE impaired VD-induced expression of cathelicidin and concomitant activation of autophagy during Mycobacterium tuberculosis (Mtb) infection and facilitated intracellular Mtb growth in human macrophages. An EP4 agonist also significantly promoted Mtb survival in human macrophages. Our results indicate that PGE inhibits hCAP18/LL-37 expression, especially VD-induced cathelicidin and autophagy, which may reduce host defense against Mtb. Accordingly, antagonists of EP4 may constitute a novel adjunctive therapy in Mtb infection.-Wan, M., Tang, X., Rekha, R. S., Muvva, S. S. V. J. R., Brighenti, S., Agerberth, B., Haeggström, J. Z. Prostaglandin E suppresses hCAP18/LL-37 expression in human macrophages via EP2/EP4: implications for treatment of Mycobacterium tuberculosis infection.
前列腺素 (PG)E 是一种花生四烯酸衍生的脂质介质，在炎症和免疫中发挥重要作用。在这项研究中，我们证明 PGE 通过 E 前列腺素 (EP)2 和 EP4 受体抑制基础和 1,25-二羟维生素 D (VD) 诱导的 hCAP18/LL-37 的表达。在人类中，VD 上调维生素 D 受体 (VDR) 的表达并促进 cathelicidin hCAP18/LL-37 基因的转录，而 PGE 则抵消了这种作用。我们发现 PGE 诱导 cAMP/PKA 信号通路并增强抑制性转录因子 cAMP 反应元件调节剂/诱导型 cAMP 早期阻遏物的表达，从而阻止 VDR 的表达和 hCAP18/LL-37 在人类巨噬细胞中的诱导。PGE 的负调控在 M1 和 M2 极化的人类巨噬细胞中很明显，尽管 PGE 在 M2 细胞中表现出更强的抑制作用。PGE 损害了 VD 诱导的分枝杆菌 (Mtb) 感染期间 cathelicidin 的表达和自噬的激活，并促进了人类巨噬细胞中内源性 Mtb 的生长。EP4 激动剂也显著促进了人类巨噬细胞中 Mtb 的存活。我们的研究结果表明，PGE 抑制 hCAP18/LL-37 的表达，特别是 VD 诱导的 cathelicidin 和自噬，这可能会降低宿主对 Mtb 的防御能力。因此，EP4 的拮抗剂可能成为 Mtb 感染的一种新的辅助治疗方法。-万，M.，唐，X.，雷卡，R. S.，穆瓦瓦，S. S. V. J. R.，布里根蒂，S.，阿杰尔伯，B.，黑格斯特伦，J. Z. 前列腺素 E 通过 EP2/EP4 抑制人巨噬细胞中 hCAP18/LL-37 的表达：对治疗分枝杆菌感染的影响。
