Divergent effect of Birinapant, and BV6 SMAC mimetic on TNFα induced NF-κB signaling and cell viability in activated hepatic stellate cells.
Mol Biol Rep
; 50(3): 2107-2117, 2023 Mar.
Article
en En
| MEDLINE
| ID: mdl-36542236
ABSTRACT
BACKGROUND:
Tumor necrosis factor-α (TNFα) is a pleiotropic cytokine involved in nuclear factor kappa B (NF-κB) mediated cell survival as well as cell death. High serum TNFα levels correlate with liver fibrosis and enhance hepatic stellate cell (HSC) viability. However, the regulatory role of cellular inhibitor of apoptosis-1/2 (cIAP1/2) during TNFα induced NF-κB signaling in activated HSCs is largely unknown. METHOD ANDRESULTS:
Activated HSCs were treated with cIAP1/2 inhbitiors i.e., SMAC mimetic BV6, and Birinapant in the presence of TNFα and macrophage conditioned media. TNFα cytokine increased cIAP2 expression and enhanced cell viability through the canonical NF-κB signaling in activated HSCs. cIAP2 inhibition via BV6 decreased the TNFα induced canonical NF-κB signaling, and reduced cell viability in activated HSCs. SMAC mimetic, Birinapant alone did not affect the cell viability but treatment of TNFα sensitized HSCs with Birinapant induced cell death. While BV6 mediated cIAP2 ablation was able to decrease the TNFα induced canonical NF-κB signaling, this effect was not observed with Birinapant treatment. Secreted TNFα from M1 polarized macrophages sensitized activated HSCs to BV6 or Birinapant mediated cell death. However, M2 polarized macrophage conditioned medium rescued the activated HSCs from BV6 mediated cytotoxicity.CONCLUSION:
In this study, we describe the regulatory role of cIAP2 in TNFα induced NF-κB signaling in activated HSCs. Targeting cIAP2 may be a promising approach for liver fibrosis treatment via modulating NF-κB signaling in activated HSCs.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
FN-kappa B
/
Factor de Necrosis Tumoral alfa
Idioma:
En
Revista:
Mol Biol Rep
Año:
2023
Tipo del documento:
Article
País de afiliación:
India