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Article

Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection

1
Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou 510642, China
2
College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
3
Zhaoqing Branch, Center of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing 526000, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Clara Balsano
Int. J. Mol. Sci. 2021, 22(11), 5646; https://doi.org/10.3390/ijms22115646
Received: 22 March 2021 / Revised: 8 May 2021 / Accepted: 20 May 2021 / Published: 26 May 2021
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)
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. View Full-Text
Keywords: coronavirus; unfolded protein response; integrated stress response; eIF2α; AP-1 family proteins; cJUN and cFOS; proinflammatory cytokine; interleukin-8 coronavirus; unfolded protein response; integrated stress response; eIF2α; AP-1 family proteins; cJUN and cFOS; proinflammatory cytokine; interleukin-8
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MDPI and ACS Style

Zhu, Q.C.; Li, S.; Yuan, L.X.; Chen, R.A.; Liu, D.X.; Fung, T.S. Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection. Int. J. Mol. Sci. 2021, 22, 5646. https://doi.org/10.3390/ijms22115646

AMA Style

Zhu QC, Li S, Yuan LX, Chen RA, Liu DX, Fung TS. Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection. International Journal of Molecular Sciences. 2021; 22(11):5646. https://doi.org/10.3390/ijms22115646

Chicago/Turabian Style

Zhu, Qing C., Shumin Li, Li X. Yuan, Rui A. Chen, Ding X. Liu, and To S. Fung 2021. "Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection" International Journal of Molecular Sciences 22, no. 11: 5646. https://doi.org/10.3390/ijms22115646

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