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Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis.

ABSTRACT:

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Kaposi's sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.

SUBMITTER: Chen L

PROVIDER: S-EPMC10790708 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis.

Chen Luping L Ding Ling L Wang Xian X Huang Yufei Y Gao Shou-Jiang S-J

mBio 20231220 1

<h4>Importance</h4>Kaposi's sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumor ...[more]

PMID: 38117084

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Project description:The hallmark of Kaposi’s sarcoma (KS), the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, is hyperinflammation. However, the role of inflammation and the mechanism of induction of inflammation in KSHV-induced cancer remain unclear. In a previous high-throughput screening against KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents. Among them, dexamethasone, a common anti-inflammatory corticosteroid, functions through binding to and activating glucocorticoid receptor (GR). In this study, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, the interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family, implicated in a wide variety of inflammatory diseases, were the most induced and suppressed cytokines in KSHV-transformed KMM cells compared to the matched primary MM cells, respectively. By using reverse genetics, we showed that KSHV-encoded miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, the GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Importantly, dexamethasone treatment inhibited cell proliferation, and colony formation in softagar of KMM cells but had a minimal effect on MM cells. Consequently, dexamethasone suppressed the initiation and growth of KS-like KMM tumors in mice. Mechanistically, dexamethasone suppressed IL-1α expression but induced IL-1Ra expression. Treatment with recombinant IL-1α protein was sufficient to rescue the inhibitory effect of dexamethasone while overexpression of IL-1Ra alone caused a weak growth inhibition of KMM cells. Furthermore, dexamethasone induced IκBα expression resulting in the inhibition of the classical and alternative NF-kB pathways and IL-1α expression. Taken together, these results revealed the important role of IL-1 signaling pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling. This study determined the mechanism of inflammation in KSHV-induced oncogenesis and identified IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.

Project description:Management of pain in the treatment of rheumatoid arthritis (RA) is a priority that is not fully addressed by the conventional therapies. In the present study, we evaluated the efficacy of cannabinoid receptor 2 (CB2) agonist JWH-015 using RA synovial fibroblasts (RASFs) obtained from patients diagnosed with RA and in a rat adjuvant-induced arthritis (AIA) model of RA. Pretreatment of human RASFs with JWH-015 (10-20 μM) markedly inhibited the ability of pro-inflammatory cytokine interleukin-1β (IL-1β) to induce production of IL-6 and IL-8 and cellular expression of inflammatory cyclooxygenase-2 (COX-2). JWH-015 was effective in reducing IL-1β-induced phosphorylation of TAK1 (Thr184/187) and JNK/SAPK in human RASFs. While the knockdown of CB2 in RASFs using siRNA method reduced IL-1β-induced inflammation, JWH-015 was still effective in eliciting its anti-inflammatory effects despite the absence of CB2, suggesting the role of non-canonical or an off-target receptor. Computational studies using molecular docking and molecular dynamics simulations showed that JWH-105 favorably binds to glucocorticoid receptor (GR) with the binding pose and interactions similar to its well-known ligand dexamethasone. Furthermore, knockdown of GR using siRNA abrogated JWH-015's ability to reduce IL-1β-induced IL-6 and IL-8 production. In vivo, administration of JWH-015 (5 mg/kg, daily i.p. for 7 days at the onset of arthritis) significantly ameliorated AIA in rats. Pain assessment studies using von Frey method showed a marked antinociception in AIA rats treated with JWH-015. In addition, JWH-015 treatment inhibited bone destruction as evident from micro-CT scanning and bone analysis on the harvested joints and modulated serum RANKL and OPG levels. Overall, our findings suggest that CB2 agonist JWH-015 elicits anti-inflammatory effects partly through GR. This compound could further be tested as an adjunct therapy for the management of pain and tissue destruction as a non-opioid for RA.

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Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis.

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Publications

Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis.

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