Alendronate Augments Lipid A –Induced IL-1α Release via Activation of ASC but Not Caspase-11

AbstractNitrogen-containing bisphosphonates (NBPs), such as alendronate (ALN), are anti-bone-resorptive drugs that have inflammatory side effects. We previously reported that ALN augmented lipid A –induced interleukin (IL)-1β production and NOD-like receptor pyrin domain-containing-3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)-dependent cell death. The present study aimed to examine whether ALN augments lipid A–induced IL-1α release and necroptosis, which is induced by the activation of receptor-interacting protein kinase (RIPK) 3. Treatment of J774.1 cells with ALN augmented lipid A–induced IL-1α release, which was not inhibited by Ac-IETD-CHO, a caspase-8 inhibitor. ALN also activated mixed lineage kinase domain-like (MLKL), a key mediator of the n ecroptosis pathway, and upregulated the expression of caspase-11, a lipid A receptor. GSK′872, a RIPK3 inhibitor, suppressed the ALN-upregulated expression of caspase-11 and augmented lipid A–induced caspase-8 activation. Moreover, ALN induced the release of NLRP3 and ASC into culture supernatan ts. GSK′872, but not Ac-IETD-CHO, reduced the ALN-induced release of NLRP3, but not ASC, into culture supernatants, and reduced ALN-induced cell death, but not ALN-induced LDH release. Antibodies against NLRP3 and ASC upregulated caspase-11 expression in the cytosol by inhibiting ALN-induced cell death. However, pretreating cells with an antibody against ASC, but not NLRP3, before ALN addition al...
Source: Inflammation - Category: Allergy & Immunology Source Type: research