title: 1,25-Dihydroxyvitamin D3 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-γ, LPS and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] 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-γ or LPS in a fashion similar to that of other TLRs. However, TLR10 expression was differentially regulated by 1,25(OH)2D3. Surface TLR10 expression on THP-1 was significantly enhanced at 24h, reaching approximately two times the control level at 48h after treatment with 100nM 1,25(OH)2D3, while that of TLR2, 4 and 5 decreased gradually in response to treatment over time. 1,25(OH)2D3 at concentrations above 1nM markedly enhanced surface TLR10 expression, but concentrations below 1nM did not. TLR10 mRNA expression was also increased by 1,25(OH)2D3. We next screened for putative binding sites of nuclear vitamin D receptor (VDR) and its counterpart RXR-α 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-α binding site within its proximal promoter. To identify possible involvement of VDR/RXR in the 1,25(OH)2D3-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)2D3 and mainly regulated at the transcriptional level via VDR/RXR-α. 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.
authors.affiliation: Department of Biological Science, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Rewa
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Biological Science, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Jong Hyeok
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Department of Biological Science, Gachon University, Incheon 406-799, Republic of Korea. Electronic address: jykim85@gachon.ac.kr.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Kim
mesh_terms: D001665:Binding Sites; D002117:Calcitriol / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D051201:Toll-Like Receptor 10 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D030181:Vitamin D Response Element
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C475955:TLR10 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D007371:Interferon-gamma; D002117:Calcitriol
keywords: 1,25-Dihydroxyvitamin D3; Monocyte; THP-1; Toll-like receptor 10; Vitamin D receptor