1,25-dihydroxyvitamin D3 downregulates aromatase expression and inflammatory cytokines in human macrophages

CER5928
2012 Vol.30, N°6
PI 0934, PF 0938
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PMID: 23253631 [PubMed]

Received: 24/08/2012
Accepted : 05/11/2012
In Press: 17/12/2012
Published: 17/12/2012

Abstract

OBJECTIVES:
Vitamin D deficiency seems to be involved in the development and severity of autoimmune/inflammatory diseases such as rheumatoid arthritis (RA). To evaluate the influence of calcitriol (1,25-dihydroxyvitamin D3, 1,25(OH)2D3) on aromatase expression in cultures of human macrophages, as a new target for vitamin D cell modulation and pro-inflammatory cytokine production.
METHODS:
Cultures of human monocytic THP-1 cells were activated to macrophages and treated for 24 hours with 1,25(OH)2D3 (10-8M), 17β-estradiol (E2, 10-8M) both alone and in combination, in order to evaluate the effects on the intracrine estrogen metabolism. Untreated human macrophages were used as controls (basal). P450-aromatase synthesis was evaluated by immunocytochemistry (ICC) and western blot analysis (WB). The expression of P450-aromatase gene (CYP19A1) was investigated by real-time PCR (RT-PCR). Macrophage pro-inflammatory cytokines IL1-β, IL-6 and TNF-α were evaluated by ELISA and WB.
RESULTS:
In E2 untreated condition, 1,25(OH)2D3 reduced P450-aromatase synthesis and CYP19A1 gene expression in cultured cells. Moreover, pro-inflammatory cytokine production (IL1-β, IL-6 and TNF-α) was significantly reduced by 1,25(OH)2D3 treatment (p<0.001 vs. basal for all cytokines). However, 1,25(OH)2D3 was found to significantly downregulate the E2-mediated increase in P450-aromatase synthesis and gene expression (p<0.001 for both vs. E2-treated macrophages), as well as the production of all pro-inflammatory cytokines (p<0.001 vs. E2-treated cells).
CONCLUSIONS:
Our data suggest that 1,25(OH)2D3 may downregulate the pro-inflammatory cytokine production in human activated macrophages by significantly decreasing the aromatase activity, especially in presence of an estrogenic milieu such as in the RA synovial tissue.