title: An antimicrobial peptide with angiogenic properties, AG-30/5C, activates human mast cells through the MAPK and NF-κB pathways.
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.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Kazo
authors.initials: K
authors.lastname: Kanazawa
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. francois@juntendo.ac.jp.|Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan. francois@juntendo.ac.jp.
authors.forename: François
authors.initials: F
authors.lastname: Niyonsaba
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D037342:Pertussis Toxin / Q000276:immunology; D015398:Signal Transduction
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D018836:Inflammation Mediators; D008055:Lipids; D016328:NF-kappa B; C542514:antimicrobial peptide AG-30; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases
keywords: Antimicrobial peptide; Inflammation; MAPK/NF-κB; Mast cell; Wound healing