Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis
Hyperinflammation is the hallmark of Kaposi's sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling, and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of NF-κB pathway and IL-1α expression. These results reveal an important role of IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 14. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Luping [VerfasserIn] |
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| Links: |
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| Themen: |
Dexamethasone |
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| Anmerkungen: |
Date Revised 10.02.2024 published: Electronic UpdateIn: mBio. 2023 Dec 20;:e0301123. - PMID 38117084 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.11.10.566578 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36505481X |
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| 500 | |a UpdateIn: mBio. 2023 Dec 20;:e0301123. - PMID 38117084 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Hyperinflammation is the hallmark of Kaposi's sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling, and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of NF-κB pathway and IL-1α expression. These results reveal an important role of IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a Dexamethasone | |
| 650 | 4 | |a Glucocorticoid receptor (GR) signaling | |
| 650 | 4 | |a IL-1 receptor antagonist | |
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| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Interleukin-1 alpha | |
| 650 | 4 | |a KS | |
| 650 | 4 | |a KSHV | |
| 650 | 4 | |a Kaposi’s sarcoma | |
| 650 | 4 | |a Kaposi’s sarcoma-associated herpesvirus | |
| 650 | 4 | |a NF-κB | |
| 700 | 1 | |a Ding, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xian |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yufei |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Shou-Jiang |e verfasserin |4 aut | |
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