title: CCL28 has dual roles in mucosal immunity as a chemokine with broad-spectrum antimicrobial activity.
abstract: CCL28 is a CC chemokine signaling via CCR10 and CCR3 that is selectively expressed in certain mucosal tissues such as exocrine glands, trachea, and colon. Notably, these tissues commonly secrete low-salt fluids. RT-PCR analysis demonstrated that salivary glands expressed CCL28 mRNA at the highest levels among various mouse tissues. Single cells prepared from mouse parotid glands indeed contained a major fraction of CD3(-)B220(low) cells that expressed CCR10 at high levels and CCR3 at low levels and responded to CCL28 in chemotaxis assays. Morphologically, these cells are typical plasma cells. By immunohistochemistry, acinar epithelial cells in human and mouse salivary glands were strongly positive for CCL28. Furthermore, human saliva and milk were found to contain CCL28 at high concentrations. Moreover, the C terminus of human CCL28 has a significant sequence similarity to histatin-5, a histidine-rich candidacidal peptide in human saliva. Subsequently, we demonstrated that human and mouse CCL28 had a potent antimicrobial activity against Candida albicans, Gram-negative bacteria, and Gram-positive bacteria. The C-terminal 28-aa peptide of human CCL28 also displayed a selective candidacidal activity. In contrast, CCL27, which is most similar to CCL28 and shares CCR10, showed no such potent antimicrobial activity. Like most other antimicrobial peptides, CCL28 exerted its antimicrobial activity in low-salt conditions and rapidly induced membrane permeability in target microbes. Collectively, CCL28 may play dual roles in mucosal immunity as a chemoattractant for cells expressing CCR10 and/or CCR3 such as plasma cells and also as a broad-spectrum antimicrobial protein secreted into low-salt body fluids.
authors.affiliation: Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Hieshima
authors.forename: Haruo
authors.initials: H
authors.lastname: Ohtani
authors.forename: Michiko
authors.initials: M
authors.lastname: Shibano
authors.forename: Dai
authors.initials: D
authors.lastname: Izawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Shiba
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shiota
authors.forename: Fuminori
authors.initials: F
authors.lastname: Katou
authors.forename: Takuya
authors.initials: T
authors.lastname: Saito
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019742:Chemokines, CC / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D054808:Histatins; D006801:Humans; D018928:Immunity, Mucosal; D007774:Lactation; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D008895:Milk, Human / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D010306:Parotid Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D054447:Receptors, CCR10; D019707:Receptors, Chemokine / Q000096:biosynthesis; D012463:Saliva / Q000276:immunology / Q000378:metabolism; D012471:Salivary Proteins and Peptides / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013295:Streptococcus mutans / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; C414047:CCL28 protein, human; C515706:CCR10 protein, human; C515707:Ccr10 protein, mouse; D018925:Chemokines; D019742:Chemokines, CC; C068075:HTN3 protein, human; D054808:Histatins; D010446:Peptide Fragments; D054447:Receptors, CCR10; D019707:Receptors, Chemokine; D012471:Salivary Proteins and Peptides