title: Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages.
abstract: Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Do-Wan
authors.initials: DW
authors.lastname: Shim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Kang-Hyuck
authors.initials: KH
authors.lastname: Heo
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Young-Kyu
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Sim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Tae-Bong
authors.initials: TB
authors.lastname: Kang
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Jae-Wan
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Sim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Cheong
authors.affiliation: Division of Food Bioscience, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Seung-Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chungbuk, Republic of Korea.
authors.forename: Jeong-Kyu
authors.initials: JK
authors.lastname: Bang
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Won
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk, Republic of Korea.
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D010455:Peptides; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C077623:Ptgs2 protein, mouse