Divergent effect of Birinapant, and BV6 SMAC mimetic on TNFα induced NF-κB signaling and cell viability in activated hepatic stellate cells

Background Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine involved in nuclear factor kappa B (NF-kappa B) mediated cell survival as well as cell death. High serum TNF alpha 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 TNF alpha induced NF-kappa B signaling in activated HSCs is largely unknown. Method and Results Activated HSCs were treated with cIAP1/2 inhbitiors i.e., SMAC mimetic BV6, and Birinapant in the presence of TNF alpha and macrophage conditioned media. TNF alpha cytokine increased cIAP2 expression and enhanced cell viability through the canonical NF-kappa B signaling in activated HSCs. cIAP2 inhibition via BV6 decreased the TNF alpha induced canonical NF-kappa B signaling, and reduced cell viability in activated HSCs. SMAC mimetic, Birinapant alone did not affect the cell viability but treatment of TNF alpha sensitized HSCs with Birinapant induced cell death. While BV6 mediated cIAP2 ablation was able to decrease the TNF alpha induced canonical NF-kappa B signaling, this effect was not observed with Birinapant treatment. Secreted TNF alpha 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 TNF alpha induced NF-kappa B signaling in activated HSCs. Targeting cIAP2 may be a promising approach for liver fibrosis treatment via modulating NF-kappa B signaling in activated HSCs.