PDF(Pubmed)
Abstract：
The only human cathelicidin, LL-37, is a host defense antimicrobial peptide with antimicrobial activities against protozoans, fungi, Gram(+) and Gram(-) bacteria, and enveloped viruses. It has been shown in experiments in vitro that LL-37 is able to induce the production of various inflammatory and anti-inflammatory cytokines and chemokines by different human cell types. However, it remains an open question whether such cytokine induction is physiologically relevant, as LL-37 exhibited its immunomodulatory properties at concentrations that are much higher (>20 μg/mL) than those observed in non-inflamed tissues (1-5 μg/mL). In the current study, we assessed the permeability of LL-37 across the Caco-2 polarized monolayer and showed that this peptide could pass through the Caco-2 monolayer with low efficiency, which predetermined its low absorption in the gut. We showed that LL-37 at low physiological concentrations (<5 μg/mL) was not able to directly activate monocytes. However, in the presence of polarized epithelial monolayers, LL-37 is able to activate monocytes through the MAPK/ERK signaling pathway and induce the production of cytokines, as assessed by a multiplex assay at the protein level. We have demonstrated that LL-37 is able to fulfill its immunomodulatory action in vivo in non-inflamed tissues at low physiological concentrations. In the present work, we revealed a key role of epithelial-immune cell crosstalk in the implementation of immunomodulatory functions of the human cathelicidin LL-37, which might shed light on its physiological action in vivo.
摘要：
唯一的人类导管素,LL-37是一种宿主防御抗菌肽，对原生动物具有抗菌活性，真菌,革兰氏（+）和革兰氏（-）细菌，和包膜病毒。体外实验表明,LL-37能够诱导不同人细胞类型产生各种炎性和抗炎细胞因子和趋化因子。然而,这种细胞因子诱导是否与生理相关仍然是一个悬而未决的问题，LL-37在浓度远高于(>20μg/mL)的非炎症组织(1-5μg/mL)时显示其免疫调节特性。在目前的研究中,我们评估了LL-37穿过Caco-2极化单层的通透性，并表明该肽可以低效率通过Caco-2单层，这决定了它在肠道中的低吸收。我们表明,低生理浓度(<5μg/mL)的LL-37不能直接激活单核细胞。然而,在极化的上皮单层存在下，LL-37能够通过MAPK/ERK信号通路激活单核细胞,诱导细胞因子的产生,通过蛋白质水平的多重测定进行评估。我们已经证明LL-37能够在低生理浓度下在非发炎组织中实现其体内免疫调节作用。在目前的工作中,我们揭示了上皮免疫细胞串扰在人cathelicidinLL-37的免疫调节功能的实现中的关键作用，这可能揭示了其在体内的生理作用。
