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An antimicrobial peptide with angiogenic properties, AG-30/5C, activates human mast cells through the MAPK and NF-κB pathways

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Abstract

Apart from their direct antimicrobial activities against invading pathogens, antimicrobial peptides exhibit additional protective functions that have led to their being named host defense peptides (HDPs). These functions include the stimulation of the production of cytokines/chemokines, the promotion of chemotaxis and cell proliferation and the induction of angiogenesis and wound healing. AG-30/5C is a novel angiogenic HDP that in addition to its antimicrobial activity also activates fibroblasts and endothelial cells and promotes angiogenesis and wound healing. Given that mast cells are found primarily in the vicinity of vessels, where they are intimately involved in wound healing, we hypothesized that AG-30/5C may activate mast cells. We demonstrated that AG-30/5C activated LAD2 human mast cells to degranulate and produce lipid mediators including leukotriene C4, prostaglandin D2 and E2. Moreover, AG-30/5C increased mast cell chemotaxis and induced the production of the cytokines GM-CSF and TNF-α and various chemokines, such as IL-8, MCP-1, MCP-3, MIP-1α and MIP-1β. The chemotaxis and cytokine/chemokine production induced by AG-30/5C were suppressed by both pertussis toxin and U-73122, suggesting the involvement of the G protein and phospholipase C pathways in AG-30/5C-induced mast cell activation. Furthermore, these pathways were activated downstream of the MAPK and NF-κB signaling molecules, as demonstrated by the inhibitory effects of ERK-, JNK-, p38- and NF-κB-specific inhibitors on cytokine/chemokine production. Interestingly, AG-30/5C caused the phosphorylation of MAPKs and IκB. We suggest that the angiogenic and antimicrobial peptide AG-30/5C plays a key role in the recruitment and activation of human mast cells at inflammation and wound sites.

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Abbreviations

AG-30/5C:

Angiogenic peptide-30/5C

EIA:

Enzyme immunoassay

ERK:

Extracellular signal-regulated kinase

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

hBD:

Human β-defensin

HDP:

Host defense peptide

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

References

  1. Hancock RE, Chapple DS. Peptide antibiotics. Antimicrob Agents Chemother. 1999;43(6):1317–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Niyonsaba F, Nagaoka I, Ogawa H. Human defensins and cathelicidins in the skin: beyond direct antimicrobial properties. Crit Rev Immunol. 2006;26(6):545–76.

    Article  CAS  PubMed  Google Scholar 

  3. Niyonsaba F, Nagaoka I, Ogawa H, Okumura K. Multifunctional antimicrobial proteins and peptides: natural activators of immune systems. Curr Pharm Des. 2009;15(21):2393–413.

    Article  CAS  PubMed  Google Scholar 

  4. Oppenheim JJ, Yang D. Alarmins: chemotactic activators of immune responses. Curr Opin Immunol. 2005;17(4):359–65.

    Article  CAS  PubMed  Google Scholar 

  5. Scott MG, Dullaghan E, Mookherjee N, Glavas N, Waldbrook M, Thompson A, et al. An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol. 2007;25(4):465–72.

    Article  CAS  PubMed  Google Scholar 

  6. Diamond G, Beckloff N, Weinberg A, Kisich KO. The roles of antimicrobial peptides in innate host defense. Curr Pharm Des. 2009;15(21):2377–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nishikawa T, Nakagami H, Maeda A, Morishita R, Miyazaki N, Ogawa T, et al. Development of a novel antimicrobial peptide, AG-30, with angiogenic properties. J Cell Mol Med. 2009;13(3):535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nakagami H, Nishikawa T, Tamura N, Maeda A, Hibino H, Mochizuki M, et al. Modification of a novel angiogenic peptide, AG30, for the development of novel therapeutic agents. J Cell Mol Med. 2012;16(7):1629–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10(6):440–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005;23:749–86.

    Article  CAS  PubMed  Google Scholar 

  11. Kunder CA, St John AL, Abraham SN. Mast cell modulation of the vascular and lymphatic endothelium. Blood. 2011;118(20):5383–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wulff BC, Wilgus TA. Mast cell activity in the healing wound: more than meets the eye? Exp Dermatol. 2013;22(8):507–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Niyonsaba F, Ushio H, Hara M, Yokoi H, Tominaga M, Takamori K, et al. Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. J Immunol. 2010;184(7):3526–34.

    Article  CAS  PubMed  Google Scholar 

  14. Niyonsaba F, Someya A, Hirata M, Ogawa H, Nagaoka I. Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D(2) production from mast cells. Eur J Immunol. 2001;31(4):1066–75.

    Article  CAS  PubMed  Google Scholar 

  15. Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology. 2002;106(1):20–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen X, Niyonsaba F, Ushio H, Hara M, Yokoi H, Matsumoto K, et al. Antimicrobial peptides human beta-defensin (hBD)-3 and hBD-4 activate mast cells and increase skin vascular permeability. Eur J Immunol. 2007;37(2):434–44.

    Article  CAS  PubMed  Google Scholar 

  17. Pundir P, Kulka M. The role of G protein-coupled receptors in mast cell activation by antimicrobial peptides: is there a connection? Immunol Cell Biol. 2010;88(6):632–40.

    Article  CAS  PubMed  Google Scholar 

  18. Wong CK, Tsang CM, Ip WK, Lam CW. Molecular mechanisms for the release of chemokines from human leukemic mast cell line (HMC)-1 cells activated by SCF and TNF-alpha: roles of ERK, p38 MAPK, and NF-κB. Allergy. 2006;61(3):289–97.

    Article  CAS  PubMed  Google Scholar 

  19. Noli C, Miolo A. The mast cell in wound healing. Vet Dermatol. 2001;12(6):303–13.

    Article  CAS  PubMed  Google Scholar 

  20. Coneely J, Kennelly R, Bouchier-Hayes D, Winter DC. Mast cell degranulation is essential for anastomotic healing in well perfused and poorly perfused rat colon. J Surg Res. 2010;164(1):e73–6.

    Article  PubMed  Google Scholar 

  21. van der Veer WM, Bloemen MC, Ulrich MM, Molema G, van Zuijlen PP, Middelkoop E, et al. Potential cellular and molecular causes of hypertrophic scar formation. Burns. 2009;35(1):15–29.

    Article  PubMed  Google Scholar 

  22. Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA. Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol. 2012;132(2):458–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601.

    Article  PubMed  Google Scholar 

  24. Williams CM, Galli SJ. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J Exp Med. 2000;192(3):455–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mann A, Niekisch K, Schirmacher P, Blessing M. Granulocyte-macrophage colony-stimulating factor is essential for normal wound healing. J Investig Dermatol Symp Proc. 2006;11(1):87–92.

    Article  CAS  PubMed  Google Scholar 

  26. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001;69(4):513–21.

    CAS  PubMed  Google Scholar 

  27. Engelhardt E, Toksoy A, Goebeler M, Debus S, Brocker EB, Gillitzer R. Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol. 1998;153(6):1849–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bousquenaud M, Schwartz C, Leonard F, Rolland-Turner M, Wagner D, Devaux Y. Monocyte chemotactic protein 3 is a homing factor for circulating angiogenic cells. Cardiovasc Res. 2012;94(3):519–25.

    Article  CAS  PubMed  Google Scholar 

  29. Johnatty RN, Taub DD, Reeder SP, Turcovski-Corrales SM, Cottam DW, Stephenson TJ, et al. Cytokine and chemokine regulation of proMMP-9 and TIMP-1 production by human peripheral blood lymphocytes. J Immunol. 1997;158(5):2327–33.

    CAS  PubMed  Google Scholar 

  30. Ferry X, Brehin S, Kamel R, Landry Y. G protein-dependent activation of mast cell by peptides and basic secretagogues. Peptides. 2002;23(8):1507–15.

    Article  CAS  PubMed  Google Scholar 

  31. Shakoory B, Fitzgerald SM, Lee SA, Chi DS, Krishnaswamy G. The role of human mast cell-derived cytokines in eosinophil biology. J Interferon Cytokine Res. 2004;24(5):271–81.

    Article  CAS  PubMed  Google Scholar 

  32. Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H. The human beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes. J Immunol. 2005;175(3):1776–84.

    Article  CAS  PubMed  Google Scholar 

  33. Smithrithee R, Niyonsaba F, Kiatsurayanon C, Ushio H, Ikeda S, Okumura K, et al. Human beta-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes. J Dermatol Sci. 2015;77(1):46–53.

    Article  CAS  PubMed  Google Scholar 

  34. Babolewska E, Brzezinska-Blaszczyk E. Human-derived cathelicidin LL-37 directly activates mast cells to proinflammatory mediator synthesis and migratory response. Cell Immunol. 2015;293(2):67–73.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to express our deepest gratitude to all 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 supported in part 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 by 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

    Kazo Kanazawa, Ko Okumura, Hideoki Ogawa & François Niyonsaba

  2. Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan

    François Niyonsaba

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  1. Kazo Kanazawa
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  2. Ko Okumura
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  3. Hideoki Ogawa
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  4. François Niyonsaba
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Correspondence to François Niyonsaba.

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Kanazawa, K., Okumura, K., Ogawa, H. et al. An antimicrobial peptide with angiogenic properties, AG-30/5C, activates human mast cells through the MAPK and NF-κB pathways. Immunol Res 64, 594–603 (2016). https://doi.org/10.1007/s12026-015-8759-5

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