1,25-Dihydroxyvitamin D-3 up-regulates TLR10 while down-regulating TLR2, 4, and 5 in human monocyte THP-1

Abstract

In humans, there are ten Toll-like receptors (TLRs), among which TLR10 is the only orphan receptor whose function is unknown. In this study, we examined the effects of IFN-gamma, LPS and 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)O-3] on TLR10 expression of human monocyte THP-1 and compared them with those of other surface TLRs such as TLR2, 4 and 5 to differentiate TLR10 from other TLRs. Surface TLR10 expression on THP-1 was significantly enhanced by the addition of IFN-gamma or LPS in a fashion similar to that of other TLRs. However, TLR10 expression was differentially regulated by 1,25(OH)(2)D-3. Surface TLR10 expression on THP-1 was significantly enhanced at 24 h, reaching approximately two times the control level at 48 h after treatment with 100 nM 1,25(OH)(2)D-3, while that of TLR2, 4 and 5 decreased gradually in response to treatment over time. 1,25(OH)(2)D-3 at concentrations above 1 nM markedly enhanced surface TLR10 expression, but concentrations below 1 nM did not. TLR10 mRNA expression was also increased by 1,25(OH)(2)D-3. We next screened for putative binding sites of nuclear vitamin D receptor (VDR) and its counterpart RXR-alpha within promoter of TLR genes using a transcription factor binding site-prediction program. The results revealed that TLR10 is the only receptor among the tested TLRs that has both a VDR and RXR-alpha binding site within its proximal promoter. To identify possible involvement of VDR/RXR in the 1,25(OH)(2)D-3-induced TLR10 up-regulation, we engaged the VDR synthesis inhibitor, dexamethasone, and the RXR antagonist, 1,8-dihydroxyanthraquinone. We found that TLR10 up-regulation was significantly blocked with pre-treatment of these inhibitors. These findings indicate that surface TLR10 expression is differentially regulated by 1,25(OH)(2)D-3 and mainly regulated at the transcriptional level via VDR/RXR-alpha. Overall, results presented herein suggest that TLR10 functions differently from other known surface TLRs under certain circumstances. Further study using primary cells is necessary to confirm the results of the present study. (C) 2014 Elsevier Ltd. All rights reserved.