Magnitude of influenza virus replication and cell damage is associated with interleukin-6 production in primary cultures of human tracheal epithelium

Yamaya, Mutsuo; Nadine, Lusamba; Ota, Chiharu; Kubo, Hiroshi; Makiguchi, Tomonori; Nagatomi, Ryoichi; Nishimura, Hidekazu

doi:10.1016/j.resp.2014.07.010

Cited by 13 publications

(37 citation statements)

References 41 publications

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“…Serine protease inhibitors, including camostat, reduce production of IL-6 and TNF-α in human tracheal epithelial cells (Table 2) [12]. Furthermore, treatment of epithelial cells with an anti-IL-6 antibody attenuated cell damage in this model [40]. These findings suggest that the serine protease inhibitors may have anti-inflammatory effects in the lung, airways and other organs of patients with an influenza virus infection.…”

Section: Inhibitory Effects Of Serine Protease Inhibitors On Influenzmentioning

confidence: 89%

“…Patients infected with highly pathogenic influenza viruses experience increased viral replication and subsequent hypercytokinemia [30,39]. Influenza viral infection-induced cell damage is partly related to the magnitude of viral replication, as well as NF-κB-p65-mediated IL-6 production and caspase-3 activation [40]. Furthermore, a large number of CD8 + T cells and granzyme B + cells have been found to be expressed in autopsy lung tissue specimens from patients infected with pandemic A/H1N1 influenza virus [32].…”

Section: The Virulence Of Influenza Virusesmentioning

confidence: 99%

“…The effects of serine protease inhibitors on inflammatory cytokine release IL-6 and TNF-α are associated with disease symptoms and severity in influenza-infected patients [39,85] and with cell damage [40]. Camostat and gabexate inhibit lipopolysaccharide-induced TNF-α release from macrophages [86] and the development of influenzaassociated pneumonia in mice by inhibiting the production of cytokine, including IL-6 [87].…”

Section: Inhibitory Effects Of Serine Protease Inhibitors On Influenzmentioning

confidence: 99%

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Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Yamaya¹,

Shimotai²

2016

Clin Microbiol

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Influenza virus replication and the production of inflammatory cytokines are associated with symptoms, including fever, and exacerbation of bronchial asthma and chronic obstructive pulmonary disease. Proteolytic activation of influenza viruses by serine proteases that are produced by airway epithelial cells is essential for viral entry and replication. Transmembrane protease serine S1 member (TMPRSS) 2, TMPRSS4 and TMPRSS11D have been detected certain cells, including the human alveolar epithelial cell line A549 and the surface epithelial cells of the human nasal mucosa, the trachea, the distal airways, and the lung. Several protease inhibitors, including aprotinin, reduce influenza virus replication. We previously demonstrated the following: (1) TMPRSSs (TMPRSS2, 4, and 11D) are present in primary cultures of human tracheal epithelial cells; (2) serine protease inhibitors, such as camostat and aprotinin, reduce the influenza virus replication and the release of the cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α into cell supernatants; and (3) camostat reduces the cleavage of an influenza virus precursor protein, HA0, into the subunit HA1. These findings suggest that serine proteases expressed by human tracheal epithelial cells induce the proteolytic activation of influenza viruses and that serine protease inhibitors may reduce viral replication and the resultant production of inflammatory cytokines. Thus, serine protease inhibitors are potential candidates for anti-influenza virus drugs.Here, we review the expression of serine proteases, the role of serine proteases in influenza virus activation, and the effects of serine protease inhibitors. In this review, we aim to introduce the effects of serine proteases and their inhibitors on influenza virus infection of human airway epithelial cells by discussing the findings of previous studies performed by our group and other research groups. Furthermore, the clinical features and virulence of influenza virus infection are reviewed to clarify the association of virus replication and cytokine release with disease severity.

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Section: Inhibitory Effects Of Serine Protease Inhibitors On Influenzmentioning

confidence: 89%

Section: The Virulence Of Influenza Virusesmentioning

confidence: 99%

Section: Inhibitory Effects Of Serine Protease Inhibitors On Influenzmentioning

confidence: 99%

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Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Yamaya¹,

Shimotai²

2016

Clin Microbiol

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“…Many studies have indicated that VEGF-A and VEGFR-2 are important for tumor growth in different cancers [57-61]. Previous studies in our laboratory have shown that some ALV-J strains have stronger oncogenicity in hemangiomas than other ALV-J strains, with their higher VEGF-A and VEGFR-2 expression in vascular tissues [62]. However, further studies are required to validate the correlation between VEGF and ALV-J oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…PBLs were isolated from the anticoagulate of 21-day-old SPF chickens and maintained in RPMI 1640 supplemented with 10% FBS, penicillin-streptomycin, and pyruvic acid sodium salt. VECs were isolated from the 14-day-old SPF embryos as described previously [62], and maintained in Dulbecco's minimum essential medium (DMEM) supplemented with 20% FBS and penicillin-streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production

et al. 2016

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Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-κB-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.

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The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice

Yamaya

Shimotai

Ohkawara

et al. 2020

Journal of Medical Virology

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The effects of the clinically used protease inhibitor nafamostat on influenza virus replication have not been well studied. Primary human tracheal (HTE) and nasal (HNE) epithelial cells were pretreated with nafamostat and infected with the 2009 pandemic [A/Sendai‐H/108/2009/(H1N1) pdm09] or seasonal [A/New York/55/2004(H3N2)] influenza virus. Pretreatment with nafamostat reduced the titers of the pandemic and seasonal influenza viruses and the secretion of inflammatory cytokines, including interleukin‐6 and tumor necrosis factor‐α, in the supernatants of the cells infected with the pandemic influenza virus. HTE and HNE cells exhibited mRNA and/or protein expression of transmembrane protease serine 2 (TMPRSS2), TMPRSS4, and TMPRSS11D. Pretreatment with nafamostat reduced cleavage of the precursor protein HA0 of the pandemic influenza virus into subunit HA1 in HTE cells and reduced the number of acidic endosomes in HTE and HNE cells where influenza virus RNA enters the cytoplasm. Additionally, nafamostat (30 mg/kg/day, intraperitoneal administration) reduced the levels of the pandemic influenza virus [A/Hyogo/YS/2011 (H1N1) pdm09] in mouse lung washes. These findings suggest that nafamostat may inhibit influenza virus replication in human airway epithelial cells and mouse lungs and reduce infection‐induced airway inflammation by modulating cytokine production.

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Magnitude of influenza virus replication and cell damage is associated with interleukin-6 production in primary cultures of human tracheal epithelium

Cited by 13 publications

References 41 publications

Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Serine Proteases and their Inhibitors in Human Airway Epithelial Cells: Effects on Influenza Virus Replication and Airway Inflammation

Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production

The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice

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