title: A novel synthetic derivative of melatonin, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation.
abstract: Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases.
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Do-Wan
authors.initials: DW
authors.lastname: Shim
authors.affiliation: Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science & Technology, Ansan, Republic of Korea.
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Han
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Ji
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Cheol-Hun
authors.initials: CH
authors.lastname: Jang
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Sushruta
authors.initials: S
authors.lastname: Koppula
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea.
authors.forename: Tae-Bong
authors.initials: TB
authors.lastname: Kang
authors.affiliation: Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju, Republic of Korea. Electronic address: kwangho@kku.ac.kr.
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D051546:Cyclooxygenase 2; D007211:Indoles; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008550:Melatonin; D009569:Nitric Oxide; D010080:Oxazoles; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C526070:streptochlorin
keywords: ALI; Anti-inflammation; Inflammasome; Melatonin; Sepsis; Streptochlorin