Regulation of TREM-1 expression by 1,25-dihydroxyvitamin D3 in human monocytes/macrophages
Introduction
Triggering receptor expressed on myeloid cells (TREM)-1 is a recently identified cell surface receptor that is expressed mainly on monocytes and neutrophils [1], [2]. Its natural ligand is yet to be identified, but activation of TREM-1 using an agonistic antibody leads to the production of proinflammatory cytokines and chemokines [3], [4], [5]. In addition to the induction of cytokine production by TREM-1 engagement alone, TREM-1 can act synergistically with Toll-like receptor (TLR) to modulate inflammatory responses. The biological significance of TREM-1 as an amplifier of inflammatory response has been confirmed in studies using mouse models and with human disease causing infectious and inflammatory conditions [5], [6], [7], [8], [9]. The expression of TREM-1 is increased during myelomonocytic differentiation, and a strong expression of TREM-1 is observed in human mature peripheral blood (PB) monocytes [4], [10]. High cell-surface expression of TREM-1 was also observed in a subset of mouse blood monocytes [11]. Interestingly, in this study, TREM-1 was not expressed in bone marrow-derived macrophages (BMMs) that had differentiated for 5 days in M-CSF-containing medium. TREM-1 expression is induced by live bacteria or their cell components such as LPS [4], [5]. Furthermore, other proinflammatory molecules such as IL-1β, TNFα and PGE2 were reported to increase the expression of TREM-1 [12], [13]. However, very less was known about the non-inflammatory stimuli that induce TREM-1 expression in human monocytes, especially during their further differentiation into macrophages.
1,25-Dihydroxyviamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D3, is a secosteroid hormone that has a central function in maintaining calcium homeostasis and bone metabolism [14]. The biological effects of 1,25(OH)2D3 are mediated by its binding to vitamin D receptor (VDR), which is a member of the nuclear hormone receptor superfamily and is expressed in most cell types, including cells of the immune system. In addition to classic activities such as calcium homeostasis and bone metabolism, 1,25(OH)2D3 has important functions in the immune system [15]. 1,25(OH)2D3 stimulates differentiation of monocyte precursors into more mature monocytes/macrophages. 1,25(OH)2D3 contributes to the host immune response through the induction of the antimicrobial peptide cathelicidin (LL-37), thereby promoting monocyte killing of Mycobacterium tuberculosis [16]. Previously, upregulated expression of TREM-1 was reported in U937 cells differentiated with 1,25(OH)2D3 [10]. This finding suggests the possibility that, in addition to the induction of antimicrobial peptide, 1,25(OH)2D3 regulates the innate immune response by upregulating of TREM-1 expression. However, in that study, the authors focused on the regulation of TREM-1 expression during myelomonocytic differentiation and did not investigate the regulatory effects of 1,25(OH)2D3 on TREM-1 expression in human mature monocytes/macrophages.
In the present study, we examined the effects of 1,25(OH)2D3 on TREM-1 expression and its regulatory roles in human mature monocyte/macrophages.
Section snippets
Materials
Phorbol 12-myristate 13-acetate (PMA), PD98059, SB203580, LY294001, MG132, Bay 11-7082, 1,25(OH)2D3, actinomycin D, cycloheximide, polymyxin B and lipopolysaccharide (LPS) from Salmonella enterica serotype enteritidis were purchased from Sigma–Aldrich (St. Louis, MO). Stock solution of 1,25(OH)2D3 was prepared in ethanol. Human M-CSF was purchased from PeproTech (Rocky Hill, NJ). Agonistic mouse monoclonal anti-human TREM-1 antibody, mouse IgG1 isotype control, phycoerythrin (PE) conjugated
Enhanced expression of TREM-1 in human monocytes/macrophages by 1,25(OH)2D3
TREM-1 is expressed barely or not at all in undifferentiated U937 cells, whereas a high level of expression is detected in U937 cells differentiated with 1,25(OH)2D3 and recombinant human TGF-β1 [10]. To determine the effect of 1,25(OH)2D3 on the expression of TREM-1 in human monocytes/macrophages, we treated the PMA-differentiated U937, peripheral blood monocytes, and RA synovial fluid macrophages with 10 nM 1,25(OH)2D3. As shown in Fig. 1A, expression of TREM-1 increased in both fresh and
Discussion
In this study, we examined the effect of 1,25(OH)2D3 on TREM-1 expression and function in human monocytes/macrophages. Since the supraphysiological concentrations of 1,25(OH)2D3 needed to modulate immune responses, human monocytes/macrophages were treated with 1,25(OH)2D3 at 10–20 nM. Because various immune cells, including monocytes/macrophages, express 1-α-hydroxylase (CYP27B1), these cells can reach the supraphysiological levels of 1,25(OH)2D3 needed to modulate immune responses [18]. 1,25(OH)
Conflicts of interest statement
The authors declare no conflicts of interest.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2001950 to J.D.J) and (2010-0022379 T-H.K).
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These authors contributed equally to this work.