Magenta Daniele, Sangiovanni Enrico, Basilico Nicoletta, Haynes Richard K, Parapini Silvia, Colombo Elisa, Bosisio Enrica, Taramelli Donatella, Dell'Agli Mario
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milano, Italy.
Acta Trop. 2014 Dec;140:77-83. doi: 10.1016/j.actatropica.2014.08.008. Epub 2014 Aug 19.
Malaria remains one of the world's most common infectious diseases, being responsible for more deaths than any other communicable disease except tuberculosis. There is strong evidence that tumour necrosis factor α and interleukin-1β are important contributors to the systemic disease caused by the infection with Plasmodium falciparum. Circulating levels of TNFα are increased after infection, as a consequence of stimulation of monocyte-macrophages by infected red blood cells or parasite products, as shown in vitro for the malaria pigment haemozoin. TNFα in turn enhances the synthesis of metalloproteinase-9 in monocytes and macrophages. Metalloproteinase-9 acts on the extracellular matrix but also on non-traditional substrates, including precursors of inflammatory cytokines, which are proteolytically activated and contribute to the amplification of the inflammatory response. The aim of the present work was to establish whether artemisinin and its derivatives artemisone, artesunate and dihydroartemisinin possess immuno-modulatory properties. In particular, it is necessary to evaluate their effects on mRNA levels and secretion of MMP-9 by the human monocytic cell line (THP-1 cells) stimulated by hemozoin or TNFα. 5μM of each derivative, although not artemisinin itself, induced significantly inhibited TNFα production. Artesunate, artemisone and DHA antagonized haemozoin-induced MMP-9 secretion by 25%, 24% and 50%, respectively. mRNA levels were also depressed by 14%, 20% and 27%, respectively, thus reflecting in part the effect observed on protein production. The derivatives significantly inhibited both TNFα-induced MMP-9 secretion and mRNA levels to a greater extent than haemozoin itself. Both haemozoin and TNFα increased NF-κB driven transcription by 11 and 7.7 fold, respectively. Artesunate, artemisone and DHA inhibited haemozoin-induced NF-κB driven transcription by 28%, 34%, and 49%, respectively. Similarly the derivatives, but not artemisinin, prevented TNFα-induced NF-κB driven transcription by 47-51%. The study indicates that artemisinins may attenuate the inflammatory potential of monocytes in vivo. Thus, in addition to direct anti-parasitic activities, the beneficial clinical effects of artemisinins for the treatment of malaria include the apparent ability to attenuate the inflammatory response, thus limiting the risk of progression to the more severe form of the disease, including the onset of cerebral malaria.
疟疾仍然是世界上最常见的传染病之一，除结核病外，其造成的死亡人数比任何其他传染病都多。有强有力的证据表明，肿瘤坏死因子α和白细胞介素-1β是导致恶性疟原虫感染引起的全身性疾病的重要因素。感染后，由于受感染的红细胞或寄生虫产物刺激单核细胞-巨噬细胞，TNFα的循环水平会升高，如体外对疟色素疟原虫血红素的研究所示。TNFα继而增强单核细胞和巨噬细胞中金属蛋白酶-9的合成。金属蛋白酶-9作用于细胞外基质，也作用于非传统底物，包括炎性细胞因子的前体，这些前体经蛋白水解激活后有助于放大炎症反应。本研究的目的是确定青蒿素及其衍生物蒿甲醚、青蒿琥酯和双氢青蒿素是否具有免疫调节特性。特别是，有必要评估它们对由疟原虫血红素或TNFα刺激的人单核细胞系（THP-1细胞）中MMP-9的mRNA水平和分泌的影响。每种衍生物5μM，虽然青蒿素本身没有，但能显著抑制TNFα的产生。青蒿琥酯、蒿甲醚和双氢青蒿素分别使疟原虫血红素诱导的MMP-9分泌减少25%、24%和50%。mRNA水平也分别降低了14%、20%和27%，从而部分反映了对蛋白质产生的影响。这些衍生物比疟原虫血红素本身更显著地抑制TNFα诱导的MMP-9分泌和mRNA水平。疟原虫血红素和TNFα分别使NF-κB驱动的转录增加11倍和7.7倍。青蒿琥酯、蒿甲醚和双氢青蒿素分别抑制疟原虫血红素诱导的NF-κB驱动的转录28%、34%和49%。同样，这些衍生物（但不是青蒿素）可使TNFα诱导的NF-κB驱动的转录减少47%-51%。该研究表明青蒿素可能在体内减弱单核细胞的炎症潜能。因此，除了直接的抗寄生虫活性外，青蒿素治疗疟疾的有益临床效果还包括明显减弱炎症反应的能力，从而降低发展为更严重疾病形式（包括脑型疟疾发作）的风险。
