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Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways

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Abstract

LL-37, the only member of the cathelicidin family of cationic antimicrobial peptides in humans has been shown to exhibit a wide variety of biological actions in addition to its antimicrobial activity. However, the lymphangiogenic effect of LL-37 has not been elucidated yet. In this study, we examined the effects of LL-37 on lymphangiogenesis and evaluated the underlying molecular mechanisms. LL-37 treatment significantly increased the migration and tube-like formation of human dermal lymphatic microvascular endothelial cells (HDLECs) and promoted the expression of lymphangiogenic factor in HDLECs. Treatment with LL-37 increased phosphorylation of ERK and Akt proteins in HDLECs, and pretreatment with ERK and Akt inhibitors significantly blocked the LL-37-induced HDLEC migration and tube-like formation. Furthermore, to investigate the involvement of formyl peptide receptor-like 1 (FPRL1) signaling in LL-37-induced lymphangiogenesis, HDLECs were treated with an FPRL1 antagonist. Pretreatment with the FPRL1 antagonist inhibited LL-37-induced phosphorylation of ERK and Akt proteins and attenuated LL-37-induced HDLEC migration and tube-like formation. These data indicated that LL-37 induces lymphangiogenesis in lymphatic endothelial cells via FPRL1, and the activation of the ERK and Akt-dependent signaling pathways.

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Acknowledgments

This work was in part supported by a Grant-in Aid for Scientific Research B (grant number: 17H04394); and a Grant-in Aid for Scientific Research C (grant number: 18K09687).

Funding

This work was in part supported by a Grant-in Aid for Scientific Research B (Grant Number: 17H04394); and a Grant-in Aid for Scientific Research C (Grant Number: 18K09687).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

    Takahiro Yanagisawa, Masakazu Ishii, Manami Takahashi, Kei Fujishima & Masahiro Nishimura

  2. Department of Preventive Dentistry, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

    Kei Fujishima

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  1. Takahiro Yanagisawa
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Correspondence to Masakazu Ishii.

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Yanagisawa, T., Ishii, M., Takahashi, M. et al. Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways. Mol Biol Rep 47, 6841–6854 (2020). https://doi.org/10.1007/s11033-020-05741-8

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