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

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.

SUBMITTER: Zhu QC

PROVIDER: S-EPMC8198748 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Zhu Qing Chun QC Li Shumin S Yuan Li Xia LX Chen Rui Ai RA Liu Ding Xiang DX Fung To Sing TS

International journal of molecular sciences 20210526 11

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- ...[more]

PMID: 34073283

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Project description:Evidence has shown that dysbiosis of the urinary microbiota existed in female type 2 diabetes mellitus (T2DM) patients. Perturbations of intestinal microbiota are linked to proinflammatory chemokine interleukin-8 (IL-8); however, the correlations between urinary microbiota and IL-8 are not well studied. Here, we investigated the associations between the altered urinary microbiota and urinary IL-8 in female T2DM patients. A modified four-tube midstream urine technique was used to collect urine specimens from 70 female T2DM patients and 70 matched healthy controls (HCs). Bacterial genomic DNA from urine specimens was isolated using magnetic beads and the urinary microbiota was assessed using Illumina MiSeq platform targeting on the 16S rRNA gene V3-V4 region. Urinary IL-8 was determined by enzyme linked immunosorbent assay. Subsequently, the T2DM patients were separated into urine IL-8 detectable (WIL8) and undetectable (NIL8) groups, and the composition of urinary microbiota between the two groups was compared. Meanwhile, the levels of IL-8 between the "≥HCs" group (those specific bacterial genera were more than or equal to the HCs) and the "<HCs" group (those specific bacterial genera were less than the HCs) was also compared. Of 70 urine samples from T2DM patients without urinary tract infections, 46 patients had detectable IL-8 in their urine (64.31 ± 70.43 pg/mL), while 24 patients had undetectable IL-8. Compared to the NIL8 group, 11 bacterial genera increased in the WIL8 group, including Corynebacterium, Akkermansia, Enterococcus, etc., whereas 10 genera, such as Faecalibacterium, Bacteroides, and Pseudomonas decreased. One species of Lactobacillus, Lactobacillus iners, increased obviously in the WIL8 group. The "≥HCs" group showed 17 genera increased and 16 genera decreased. In addition, 18 genera contributed to the presence of urinary IL-8 in T2DM patients, which explained 95.60% of the total variance of urinary microbiota. Our study demonstrated that dysbiosis of the urinary microbiota with several key bacteria was associated with urinary IL-8 in female T2DM patients, which might be useful to explore the interactions between urinary microbiota and inflammatory responses and shed light on novel diagnosis and therapy for urinary microbiota associated with infections in T2DM patients.

Project description:Host genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacterium Borrelia burgdorferi C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated with B. burgdorferi produce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences of B. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

Dataset Information

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

Publications

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

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