Abstract：
Concerns regarding toxicity and resistance of current drugs have been reported in visceral leishmaniasis. Anti-microbial peptides are considered as new promising candidates and amongst them, human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, coupled with its apoptosis-inducing role. Administration of hCAP18/LL-37 in infected macrophages also decreased parasite survival and increased the host favorable cytokine IL-12. However, 1,25-dihydroxyvitamin D3 (VitD3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the VitD3-receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. Present study thus documents the anti-leishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection.
摘要：
内脏利什曼病已报道了对当前药物毒性和耐药性的担忧。抗微生物肽被认为是新的有希望的候选人，其中，人cathelicidinhCAP18/LL-37对药物敏感和耐药的利什曼原虫显示出显著的寄生虫杀伤作用，再加上其诱导凋亡的作用。在感染的巨噬细胞中施用hCAP18/LL-37还降低了寄生虫的存活并增加了宿主有利的细胞因子IL-12。然而,1,25-二羟基维生素D3（VitD3）诱导的内源性hCAP18/LL-37的产生在感染的THP-1细胞中受到阻碍。感染还抑制了VitD3受体（VDR），hCAP18/LL-37的转录因子。cAMP响应元件调制器（CREM），VDR的抑制因子,在感染中诱导，导致VDR和cathelicidin表达均受到抑制。发现PGE2/cAMP/PKA轴在感染期间调节CREM诱导,并且在感染细胞和BALB/c小鼠中沉默CREM导致寄生虫存活率降低。因此，本研究记录了cathelicidin的抗利什曼原虫潜力，并进一步确定了CREM是利什曼原虫感染中cathelicidin的阻遏物。
