Abstract
Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.
Highlights
Since the start of this century, three animal coronaviruses have crossed the species barrier and caused severe disease in humans
The integrated stress response (ISR) and activator protein-1 (AP-1) family proteins are crucial for the induction of proinflammatory chemokine IL-8 in infectious bronchitis virus (IBV)-infected cells, and may be potential therapeutic targets for immunopathologies associated with coronavirus infections
To determine the induction of IL-8 during coronavirus infection, Vero and H1299 cells were infected with IBV and porcine epidemic diarrhea virus (PEDV) at MOI~2, respectively
Summary
Since the start of this century, three animal coronaviruses have crossed the species barrier and caused severe disease in humans. These proteins activate the transcription of type I/III interferons (IFN-I/III) and proinflammatory cytokines/chemokines such as tumor necrosis factoralpha (TNF-α), interleukin-6 (IL-6), and IL-8 Acting locally, these cytokines/chemokines recruit immune cells and facilitate antiviral responses; but their excessive and uncontrolled release can lead to life-threatening cytokine release syndrome (CRS) that underlies the pathogenesis of severe coronavirus diseases [12,13,14]. In cells infected with transmissible gastroenteritis virus (TGEV), PERK/eIF2α-mediated translation attenuation reduced the expression of IκBα, thereby activating NF-κB-dependent IFN-I production to suppress TGEV replication [31]. It is still uncertain how ISR contributes to the induction of proinflammatory cytokines/chemokines during coronavirus infection. The ISR and AP-1 family proteins are crucial for the induction of proinflammatory chemokine IL-8 in IBV-infected cells, and may be potential therapeutic targets for immunopathologies associated with coronavirus infections
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