Elsevier

Immunology Letters

Volume 154, Issues 1–2, July–August 2013, Pages 80-85
Immunology Letters

Regulation of TREM-1 expression by 1,25-dihydroxyvitamin D3 in human monocytes/macrophages

https://doi.org/10.1016/j.imlet.2013.08.012Get rights and content

Highlights

  • We examined the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on TREM-1 expression.

  • 1,25(OH)2D3 increased TREM-1 expression in human monocytes/macrophages.

  • 1,25(OH)2D3 modulates the innate immune responses by increasing TREM-1 expression.

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface receptor that is expressed mainly on monocytes and neutrophils, and acts as an amplifier of immune responses. In this study, 1,25(OH)2D3 strongly upregulated the expression of TREM-1 in human monocytes and macrophages. 1,25(OH)2D3 stimulated TREM-1 mRNA expression by augmenting transcription, and not by inhibiting mRNA degradation. The upregulated expression of TREM-1 by 1,25(OH)2D3 was dependent on the NF-κB signaling pathway and required new protein synthesis in differentiated U937 macrophages. Our results show that 1,25(OH)2D3 can affect the innate and inflammatory responses by upregulating TREM-1 expression, and suggest that 1,25(OH)2D3 may function as an enhancer of the innate immune response by upregulating TREM-1 expression, in addition to inducing the antimicrobial peptide cathelicidin.

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).

References (23)

  • S. Gibot et al.

    A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis

    J Exp Med

    (2004)
  • Cited by (31)

    • Triggering receptor expressed on myeloid cells-1 (TREM-1) inhibition in atherosclerosis

      2022, Pharmacology and Therapeutics
      Citation Excerpt :

      Additionally, non-immune cells, such as endothelial cells, vascular smooth muscle cells (VSMCs), and platelets, express TREM-1 (Bouchon, Dietrich, & Colonna, 2000; Boufenzer et al., 2012; Jolly et al., 2017; Wang et al., 2017b). TREM-1 gene expression is enhanced by various transcription factors, including nuclear factor kappa B (NF-κB), peroxisome proliferator-activated receptor-gamma (PPAR-γ), activator protein-1 (AP-1), PU.1, and by the effect of other factors, such as cyclic adenosine monophosphate, vitamin D receptor, angiotensin II, oxidized low density lipoprotein (LDL) and hypoxia response elements (Bosco et al., 2011; Dower, Ellis, Saraf, Jelinsky, & Lin, 2008; Hosoda, Tamura, Kida, & Nagaoka, 2011; Kim et al., 2013; Li et al., 2016; Liu, Agrawal, & Chatzizisis, 2019; Vandestienne et al., 2021; Weigelt et al., 2011; Zeng, Ornatowska, Joo, & Sadikot, 2007; Zysset et al., 2016) (Fig. 1). The structure of TREM-1 and the intracellular signaling pathways are illustrated in Fig. 1.

    • The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

      2019, Autoimmunity Reviews
      Citation Excerpt :

      Whereas, macrophage stimulation with both LPS and CpG-ODN significantly abrogated TREM-1 LPS-induced membrane upregulation [6]. TREM-1 gene transcription is positively regulated though AP-1, cAMP, NF-κB, vitamin D receptor and hypoxia response elements [20,30–33]. Whereas, the transcription factor PU.1 acts as a brake to TREM-1 expression as TREM-1 expression is suppressed by PU.1 overexpression [31,34].

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text