Chen, Luping
(2024)
Activation of Glucocorticoid Receptor Signaling Inhibits KSHV-Induced Inflammation and Tumorigenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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, which 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 treatment induced IκBα expression resulting in inhibition of the NF-κB pathway and subsequent IL-1α expression. These results reveal an important role of the 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.
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Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
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ETD Committee: |
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Date: |
16 September 2024 |
Date Type: |
Publication |
Defense Date: |
12 January 2024 |
Approval Date: |
16 September 2024 |
Submission Date: |
2 April 2024 |
Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
Number of Pages: |
134 |
Institution: |
University of Pittsburgh |
Schools and Programs: |
School of Medicine > Integrative Systems Biology |
Degree: |
PhD - Doctor of Philosophy |
Thesis Type: |
Doctoral Dissertation |
Refereed: |
Yes |
Uncontrolled Keywords: |
Kaposi’s sarcoma (KS), Kaposi’s sarcoma-associated herpesvirus (KSHV), inflammation, dexamethasone, glucocorticoid receptor (GR) signaling, interleukin-1 alpha (IL-1α), IL-1 receptor antagonist (IL-1Ra), NF-κB |
Date Deposited: |
16 Sep 2024 19:08 |
Last Modified: |
16 Sep 2024 19:08 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/45965 |
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