Inhibition of the NF-κB pathway as a candidate therapeutic strategy for cryopyrin-associated periodic syndrome

OBJECTIVES: Cryopyrin-associated periodic syndrome (CAPS) is caused by unrestricted IL-1β release due to mutation of the gene coding NLRP3. This study aimed to clarify whether NLRP3-related IL-1β release is dependent on the NF-κB pathway. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy subjects or patients with Muckle-Wells syndrome were primed with LPS and subsequently stimulated by ATP. Human umbilical vein endothelial cells (HUVECs) were cultured with the supernatant obtained from LPS-plus ATP-stimulated PBMCs. Expression of proinflammatory molecules was estimated using RT-PCR, ELISA or immunochemical staining, in the presence or absence of an NF-κB inhibitor (-)-dehydroxymethylepoxyquinomicin (DHMEQ). RESULTS: DHMEQ inhibited expression of proIL-1β and NLRP3 by normal PBMCs primed with LPS, resulting in inhibition of caspase-1 activation and IL-1β secretion by the cells after subsequent stimulation with ATP. DHMEQ also inhibited expression of IL-1β, TNFα, IL-6 and VCAM-1 by HUVECs. Patient cells released IL-1β spontaneously or by ATP-stimulation even without LPS-priming. Both the spontaneous and stimulated IL-1β releases were inhibited by DHMEQ without affecting viability of the cells. CONCLUSIONS: These results clearly indicate that IL-1β production through the NLRP3 inflammasome is dependent on the NF-κB pathway, which could be a good target for the development of a novel therapeutic strategy for CAPS.