Gene expression profiles in dendritic cells conditioned by lα,25-dihydroxyvitamin D3 analog

Inhibition of dendritic cell (DC) maturity is an important immunomodulatory effect of 1alpha,25-dihydroxyvitamin D-3 (1alpha,25(OH)(2)D-3) and related analogs (D-3 analogs). The mechanisms underlying 1alpha,25(OH)(2)D-3-mediated DC modulation are Vitamin D receptor (VDR)dependent and likely involve direct or indirect regulation of multiple genes. Gene expression profiles of bone marrow-derived DCs (BMDCs) generated in the absence or presence of a potent D-3 analog were analyzed using microarray technology. Results for D-3 analog-conditioned DCs were also compared with glucocorticoid-conditioned BMDCs and with BMDCs conditioned with D-3 analog and glucocorticoid combined. Of similar to12,000 gene products assayed, 52% were considered to have detectable expression in unconditioned BMDCs. Based on relative expression levels, 5.3% of these expressed genes were "silenced" or "suppressed" in D-3 analog-conditioned BMDCs and 2.1% were "augmented". In addition, 1.7% of gene products undetectable in control BMDCs were "induced" by D-3 analog. Functional grouping of modulated genes demonstrated important effects of D-3 analog on immunoreceptors, on chemokines and chemokine receptors, on growth factors/cytokines and related receptors, and on neuroendocrine hormones and related receptors. Many of these gene products were unaffected or differently regulated by glucocorticoid suggesting specific VDR-mediated regulatory effects. Confirmation of microarray analysis results for two differentially regulated chemokines (MIP-1alpha and RANTES) was obtained by RT-PCR and ELISA. The methodology provides novel insights into DC gene regulation by 1alpha,25(OH)(2)D-3 agonists. (C) 2004 Elsevier Ltd. All rights reserved.