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Innate defense regulator IDR-1018 activates human mast cells through G protein-, phospholipase C-, MAPK- and NF-ĸB-sensitive pathways

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Abstract

Host defense (antimicrobial) peptides not only display antimicrobial activities against numerous pathogens but also exert a broader spectrum of immune-modulating functions. Innate defense regulators (IDRs) are a class of host defense peptides synthetically developed from natural or endogenous cationic host defense peptides. Of the IDRs developed to date, IDR-1018 is more efficient not only in killing bacteria but also in regulating the various functions of macrophages and neutrophils and accelerating the wound healing process. Because mast cells intimately participate in wound healing and a number of host defense peptides involved in wound healing are also known to activate mast cells, this study aimed to investigate the effects of IDR-1018 on mast cell activation. Here, we showed that IDR-1018 induced the degranulation of LAD2 human mast cells and caused their production of leukotrienes, prostaglandins and various cytokines and chemokines, including granulocyte-macrophage colony-stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and -3, macrophage-inflammatory protein-1α and -1β, and tumor necrosis factor-α. Furthermore, IDR-1018 increased intracellular calcium mobilization and induced mast cell chemotaxis. The mast cell activation was markedly suppressed by pertussis toxin, U-73122, U0126, SB203580, JNK inhibitor II, and NF-κB activation inhibitor II, suggesting the involvement of G-protein, phospholipase C, ERK, p38, JNK and NF-κB pathways, respectively, in IDR-1018-induced mast cell activation. Notably, we confirmed that IDR-1018 caused the phosphorylation of MAPKs and IκB. Altogether, the current study suggests a novel immunomodulatory role of IDR-1018 through its ability to recruit and activate human mast cells at the sites of inflammation and wounds.

Highlights

  • We report that IDR-1018 stimulates various functions of human mast cells.

  • IDR-1018-induced mast cell activation is mediated through G protein, PLC, MAPK and NF-κB pathways.

  • IDR-1018 will be a useful therapeutic agent for wound healing.

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Abbreviations

CysLT:

cysteinyl leukotriene

EIA:

enzyme immunoassay

ELISA:

enzyme-linked immunosorbent assay

ERK:

extracellular signal-regulated kinase

GM-CSF:

granulocyte-macrophage colony-stimulating factor

IDR:

innate defense regulator

IL:

interleukin

JNK:

c-Jun N-terminal kinase

LT:

leukotriene

MAPK:

mitogen-activated protein kinase

MCP:

monocyte chemoattractant protein

MIP:

macrophage-inflammatory protein

NF-κB:

nuclear factor-κB

PG:

prostaglandin

PLC:

phospholipase C

TNF:

tumor necrosis factor

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Acknowledgements

We would like to express our deepest gratitude to all the members of the Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine for their comments and Michiyo Matsumoto for secretarial assistance. This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant number: 26461703 to F.N.) and the Atopy (Allergy) Research Center, Juntendo University, Tokyo, Japan.

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Authors and Affiliations

  1. Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Kensuke Yanashima, Panjit Chieosilapatham, Eri Yoshimoto, Ko Okumura, Hideoki Ogawa & François Niyonsaba

  2. Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Panjit Chieosilapatham

  3. Faculty of International Liberal Arts, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    François Niyonsaba

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  1. Kensuke Yanashima
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Correspondence to François Niyonsaba.

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Yanashima, K., Chieosilapatham, P., Yoshimoto, E. et al. Innate defense regulator IDR-1018 activates human mast cells through G protein-, phospholipase C-, MAPK- and NF-ĸB-sensitive pathways. Immunol Res 65, 920–931 (2017). https://doi.org/10.1007/s12026-017-8932-0

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