title: Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells.
abstract: Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3'-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3'-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-β and IFN-γ1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection.
authors.affiliation: Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.|Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Hoi-Hin
authors.initials: HH
authors.lastname: Kwok
authors.affiliation: Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.|Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Po-Ying
authors.initials: PY
authors.lastname: Poon
authors.affiliation: Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.|Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Siu-Ping
authors.initials: SP
authors.lastname: Fok
authors.affiliation: Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.|Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ying-Kit Yue
authors.affiliation: Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Nai-Ki
authors.initials: NK
authors.lastname: Mak
authors.affiliation: Centre of Influenza Research and School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Michael Chi-Wai
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Centre of Influenza Research and School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Joseph Sriyal Malik
authors.initials: JS
authors.lastname: Peiris
authors.affiliation: Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.|Department of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region.
authors.forename: Ricky Ngok-Shun
authors.initials: RN
authors.lastname: Wong
mesh_terms: D021581:Active Transport, Cell Nucleus; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology*; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053127:Influenza A Virus, H9N2 Subtype / Q000187:drug effects / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008168:Lung; D055806:Microvessels / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007211:Indoles; D050796:STAT3 Transcription Factor; D016899:Interferon-beta; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C027185:indirubin