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.
Highlights
Influenza A viruses (IAV) cause seasonal epidemics and occasional global pandemics in human populations and resulted in a substantial number of deaths and economic burden[1]
Recent studies suggested that lung endothelium is the central regulator of cytokine amplification during influenza A virus infection, while dysregulation of cytokines production may result in systemic inflammation[22]
We found that the infection of influenza A virus subtype A/Quali/Hong Kong/G1/97 (H9N2) on human pulmonary microvascular endothelial cells (HPMECs) induced excessive production of various pro-inflammatory cytokines and chemokines, including IP-10 (Fig. 1A), RANTES (Fig. 1B) and IL-6 (Fig. 1C) in a time-related manner
Summary
Influenza A viruses (IAV) cause seasonal epidemics and occasional global pandemics in human populations and resulted in a substantial number of deaths and economic burden[1]. Infection of the virus triggers an immediate innate immune response of the host cells in order to restrict the spread of the virus. Recognition of IAV by the host cell activates several intracellular signaling pathways and results in the induction of gene expression for cytokine or chemokines[10]. These cytokines and chemokines are essential in cell-cell communication and recruitment of immune cells. Recent studies on highly pathogenic avian influenza viruses like H5N1 subtype highlighted that lung endothelium are at the center of innate immune cells recruitment and excessive pro-inflammatory cytokine production during severe IAV infection[22,23,24]. Modulation of the host immune response has the potential advantage to overcome the above problems[32]
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