Vitamin D₃Metabolites Enhance the NLRP3-Dependent Secretion of IL-1β From Human THP-1 Monocytic Cells

Abstract

Vitamin D3 has emerged as an important regulator of the immune system. With metabolic enzymes for vitamin D3 activation and vitamin D receptors (VDR) now identified in a variety of immune cells, the active vitamin D3 metabolite 1,25(OH)2D3, is thought to possess immunomodulatory properties. We examined whether 1,25(OH)2D3 might also enhance the NLRP3-dependent release of mature IL-1β from macrophages. PMA-differentiated THP-1 cells were stimulated with vitamin D3 metabolites and assessed for CYP27, CYP24, NLRP3, ASC, pro-caspase-1 expression by western blot and real-time qPCR as well as inflammasome activation with pro-inflammatory cytokine IL-1β release measured by ELISA. Exposure to 1,25(OH)2D3 had no effect on the basal expression levels of VDR; however, CYP27A1 transcript was suppressed and CYP24A1 transcript was substantively elevated. Both 1,25(OH)2D3 - and 25(OH)D3 induced IL-1β release from THP-1 cells, and these effects were blocked with application of the caspase-1 inhibitor YVAD and the NLRP3 inhibitors glyburide and Bay 11-7082. Interestingly, 1,25 (OH)2D3 exposure reduced NLRP3 protein expression but had no effect on ASC or pro-caspase-1 protein levels. The increase in mature IL-1β elicited by 1,25(OH)2D3 was modest compared to that found for ATP or C. difficile toxins. However, co-treatment of THP-1 cells with ATP and 1,25(OH)2D3 resulted in more IL-1β secretion than ATP or 1,25(OH)2D3 alone.

Vitamin D reduces the serum levels of inflammatory cytokines in rat models of periodontitis and chronic obstructive pulmonary disease

“…promotes innate immunity by increasing chemotactic and phagocytic activity and production of the antimicrobial peptide cathelicidin (32). Vitamin D metabolites can also enhance interleukin-1 (IL-1) secretion through activation of inflammasomes (33). However, the present data provided further evidence for the therapeutic benefits of 25-OHD3 on COPD and periodontitis through its anti-inflammatory activity.…”

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

“…Further mechanistic research proved that VDR ligand calcitriol exert inhibiting effect on NLRP3 pathway via Nrf2 activation in human corneal epithelial cells and may serves a potential therapy of dry eye which is a common ocular surface problem (Dai et al, 2019). However, the regulatory effect of VDR ligands on NLRP3 signal and immunomodulatory properties was controversial, the study of Tulk et al (2015) Proved that 1,25(OH)2D3, a VDR active ligand, could enhance the NLRP3 activation and the secrection of its downstream proinflammatory effector IL-1β in human THP-1 monocytic cells. Given the results of several previous studies, hence, we hypothesize the existence of a close relationship between VDR and the NLRP3 inflammasome signal and assume that NLRP3 inhibition through VDR activation may induce anti-fibrosis and anti-inflammatory effects in cholestatic liver injury, which may serve as a new mechanism of the liverprotective effect of VDR.…”

Can vitamin D protect against age-related macular degeneration or slow its progression?

“…NLRP3 activation has been associated with pathogenesis of AMD and its role has been linked with autophagy (Celkova et al, 2015;Kauppinen et al, 2016). It was reported that both, 1,25(OH)2D and 25(OH)D had increased the release of IL-1α from human monocytes with this effect being dependent on caspase-1 and NLRP3 (Tulk et al, 2015).…”