Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity.
Human beta-defensins (hBDs) are crucial factors of intrinsic immunity that function in the immunologic response to a variety of invading enveloped viruses, bacteria, and fungi. hBDs can cause membrane depolarization and cell lysis due to their highly cationic nature. These molecules participate in antimicrobial defenses and the control of adaptive and innate immunity in every mammalian species and are produced by various cell types. The C-terminal 15-mer peptide within hBD3, designated as hBD3-3, was selected for study due to its cell- and skin-penetrating activity, which can induce anti-inflammatory activity in lipopolysaccharide-treated RAW 264.7 macrophages. hBD3-3 penetrated both the outer membrane of the cells and mouse skin within a short treatment period. Two other peptide fragments showed poorer penetration activity compared to hBD3-3. hBD3-3 inhibited the lipopolysaccharide-induced production of inducible nitric oxide synthase, nitric oxide, and secretory cytokines, such as interleukin-6 and tumor necrosis factor in a concentration-dependent manner. Moreover, hBD3-3 reduced the interstitial infiltration of polymorphonuclear leukocytes in a lung inflammation model. Further investigation also revealed that hBD3-3 downregulated nuclear factor kappa B-dependent inflammation by directly suppressing the degradation of phosphorylated-IκBα and by downregulating active nuclear factor kappa B p65. Our findings indicate that hBD3-3 may be conjugated with drugs of interest to ensure their proper translocation to sites, such as the cytoplasm or nucleus, as hBD3-3 has the ability to be used as a carrier, and suggest a potential approach to effectively treat inflammatory diseases.
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea.
Jue Yeon
JY
Lee
Dental Regenerative Biotechnology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Jin Sook
JS
Suh
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea.
Jung Min
JM
Kim
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea.
Jeong Hwa
JH
Kim
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea.
Hyun Jung
HJ
Park
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea ; Dental Regenerative Biotechnology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Yoon Jeong
YJ
Park
Central Research Institute, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Chungcheongbuk-do, Republic of Korea.
Chong Pyoung
CP
Chung
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023083:beta-Defensins / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D057846:Cell-Penetrating Peptides; D016207:Cytokines; C422950:DEFB103A protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
NF-κB canonical pathway; anti-inflammatory activity; cell-penetrating peptide; human beta-defensin 3; lipopolysaccharide