Elsevier

Cytokine

Volume 45, Issue 3, March 2009, Pages 190-197
Cytokine

1α,25-Dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in Human Monocytes

https://doi.org/10.1016/j.cyto.2008.12.009Get rights and content

Abstract

CD40 ligand (CD40L) stimulation induces proinflammatory and immunomodulatory activity in monocytes. Here, we report on the effects of the steroid hormone 1α,25-dihydroxyvitamin D3 (1,25D3) on human blood monocytes that have been stimulated with the CD40L ligand. Co-treatment of CD40L-stimulated monocytes with 1,25D3 resulted in reduced production and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, as well as in reduced expression of the surface co-stimulatory molecules CD80 and CD86. In addition, costimulation of CD4+ T lymphocytes by monocytes co-treated with CD40L and 1,25D3 resulted in reduced cell proliferation and diminished interferon (IFN)-γ but enhanced IL-10 production by CD4+ T cells. Finally, 1,25D3 interfered with the ability of CD40L to rescue monocytes from apoptosis induced by serum withdrawal. These findings suggest that 1,25D3 may regulate the interaction of monocytes with T cells or other cell types that express CD40L, thus influencing the outcome of the immune or inflammatory response.

Introduction

In addition to its classical role in calcium homeostasis, the hormonal, active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3), displays immunomodulatory properties in vitro as well as in vivo [1], [2]. Its actions on the immune system are exerted via intracellular receptors (VDR), present in several immunological cells such as lymphocytes and monocytes [3]. When added to mitogen-stimulated human peripheral blood lymphocytes in vitro, 1,25D3 inhibits their proliferation, Ig synthesis, and accumulation of transcripts for interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-α and -β and interferon (IFN)-γ [4], [5], [6]. 1,25D3 also affects monocyte phenotype and function. Müller et al. showed that 1,25D3 dose-dependently inhibited the production of IL-1α, IL-6, and TNF-α by lipopolysaccharide stimulated monocytes [7]. Moreover, 1,25D3 treatment reduced the basal expression HLA-DR, CD4, and CD86 and the induction of CD80 by TNF-α by monocytes [8], [9], [10]. Finally, a defect in accessory cell function which resulted in impaired capacity of monocytes to promote lectin-induced T cell activation was found in 1,25D3-treated monocytes, which was postulated to be the consequence of reduced MHC and CD80 expression [8], [11].

Monocytes occupy a central position in many inflammatory processes. As a consequence, these cells are a target for many activating cytokines/chemokines that are involved in the regulation of the inflammatory response. However, proinflammatory cytokines/chemokines share many redundant activities so that monocyte activation by these substances is mostly aspecific. More specific activation of monocytes may be achieved via processes that involve the CD40 ligand (CD40L)-CD40 pair, members of the tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamilies of molecules, respectively [12], [13], [14], [15], [16]. Engagement of CD40 with CD40L leads to the production of pro-inflammatory cytokines such as TNF-α and IL-1β and up-regulation of surface molecules (CD40, CD80, and CD86) [17], [18], [19]. Moreover, CD40 stimulation of monocytes plays a major role in the control of intracellular killing of pathogens, because large amounts of IL-12 are produced [20]. However, the induction of pro-inflammatory cytokines by CD40 triggering on monocytes has been suggested to be relevant to the pathogenesis of many autoimmune diseases such as systemic lupus erythematosus (SLE) [21], [22], rheumatoid arthritis (RA) [23], [24], [25], multiple sclerosis (MS), [26], [27] inflammatory bowel diseases (IBD) [28], glomerular inflammatory diseases, [29] and in graft-versus-host [30] and allograft rejection [31]. Blockage of the interaction of this ligand–receptor pair has resulted in a decrease in both the incidence and the severity of chronic inflammatory diseases [32], [33], [34] graft-versus-host-disease [35] and allograft rejection [36], [37]. Although it has been previously shown that 1,25D3 may interfere with CD40L-induced CD40 expression in fully differentiated monocyte-derived DC [38], there are no reports on the effect of this compound on CD40L-activated fresh monocytes.

In this study, we analyzed the effect of 1,25D3 on the CD40–CD40L stimulatory pathway of human monocytes. 1,25D3 reduced both the CD40L-induced production of pro-inflammatory cytokines, such as TNF-α and IL-1β, and the expression of the surface co-stimulatory molecules CD80 and CD86. Co-stimulation of CD4+ T lymphocytes by monocytes stimulated by CD40L in the presence of 1,25D3 resulted in reduced cell proliferation and interferon (IFN)-γ production but increased IL-10 production. Finally, 1,25D3 proved able to interfere with the ability of CD40L to rescue cultured monocytes from apoptosis induced by serum withdrawal.

Section snippets

Cells

Peripheral blood obtained from healthy donors was enriched for PBMC by centrifugation over Ficoll Hypaque. PBMC were then further enriched for monocytes by counter flow centrifugal elutriation as previously described [39]. Cells obtained by this method are >90% monocytes as determined by morphological criteria and by the expression of the CD14 antigen. Monocytes were cultured in Roswell Park Memorial Institute (RPMI)-1640 medium supplemented with 20% heat-inactivated fetal calf serum, 2 mM l

1,25D3 inhibits the cytokine response of CD40L-stimulated macrophages

First, we studied by FACS analysis the capacity of 1,25D3 to interfere with the ability of CD40L to induce cytokine production in monocytes (Fig. 1A and B). Monocytes exposed to CD40L produced detectable amount of TNF-α and IL-1β. The cytokine response induced by CD40L was strongly suppressed by 1,25D3 treatment. This suppression was significant with 1,25D3 concentrations of 0.1 nM, whereas treatment with 10 nM 1,25D3 induced maximum suppression. These data were confirmed and expanded by testing

Discussion

In agreement with several published studies [18], [20], [42], we show here that soluble CD40L alone is very effective at stimulating the production of pro-inflammatory cytokines by human monocytes. However, some discrepancies exist between our findings and those from Burger and colleagues [43] who reported that CD40L failed to induce cytokine production in the absence of IFN-γ co-stimulation. It is thought that maturation or pre-activation status of monocytes largely influence their capability

References (61)

  • C.D. Tsoukas et al.

    Inhibition of interleukin-1 production by 1,25-dihydroxyvitamin D3

    J Clin Endocrinol Metab

    (1989)
  • J.M. Lemire et al.

    1, 25-Dihydroxivitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells

    J Clin Invest

    (1984)
  • W.F. Rigby et al.

    Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3

    J Clin Invest

    (1987)
  • H. Xu et al.

    1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC-class II antigen expression, accessory activity and phagocytosis of human monocytes

    Scand J Immunol

    (1993)
  • A. Clavreul et al.

    Vitamin D differentially regulates B7.1 and B7.2 expression on human peripheral blood monocytes

    Immunology

    (1998)
  • W.F. Rigby et al.

    Decreased accessory cell function and costimulatory activity by 1,25-dihydroxyvitamin D3-treated monocytes

    Arthritis Rheumatol

    (1992)
  • D. Hollenbaugh et al.

    The role of CD40 and its ligand in the regulation of the immune response

    Immunol Rev

    (1994)
  • I.S. Grewal et al.

    The CD40 ligand: at the centre of the immune universe?

    Immunol Res

    (1997)
  • T.M. Foy et al.

    Immune regulation by CD40 and its ligand gp39

    Annu Rev Immunol

    (1996)
  • I.S. Grewal et al.

    CD40 and CD154 in cell mediated immunity

    Annu Rev Immunol

    (1998)
  • D. Graf et al.

    Cloning of TRAP, a ligand for CD40 on human T cells

    Eur J Immunol

    (1992)
  • M.R. Alderson et al.

    CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40

    J Exp Med

    (1993)
  • P.A. Kiener et al.

    Stimulation of CD40 with purified soluble gp 39 induces proinflammatory responses in human monocytes

    J Immunol

    (1995)
  • D. Chaussabel et al.

    CD40 ligation prevents trypanosoma cruzi infection through interleukin-12 upregulation

    Infect Immun

    (1999)
  • M. Koshy et al.

    Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes

    J Clin Invest

    (1996)
  • M.F. Liu et al.

    Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment

    Autoimmunity

    (2001)
  • C.R. Wang et al.

    Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis

    Clin Exp Immunol

    (2003)
  • M. Harigai et al.

    Amplification of the synovial inflammatory response through activation of mitogen-activated protein kinases and nuclear factor kappaB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

    Arthritis Rheumatol

    (2004)
  • J. Jensen et al.

    Increased T cell expression of CD154 (CD40-ligand) in multiple sclerosis

    Eur J Neurol

    (2001)
  • O. Ludwiczek et al.

    Plasma levels of soluble CD40 ligand are elevated in inflammatory bowel diseases

    Int J Colorectal Dis

    (2003)
  • Cited by (189)

    • Vitamin D and the cardiovascular system

      2023, Feldman and Pike's Vitamin D: Volume One: Biochemistry, Physiology and Diagnostics
    • Vitamin D and antiviral immunity

      2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
    • Maternal serum 25-hydroxy vitamin D levels and risk of autism spectrum and attention-deficit hyperactivity disorders in offspring: A systematic review and dose-response meta-analysis

      2023, Psychiatry Research
      Citation Excerpt :

      Immune response modification could also be involved in ASD and ADHD (Leffa et al., 2018; Masi et al., 2015; O'Shea et al., 2014). Vitamin D may protect neurodevelopment by down-regulation of pro-inflammatory cytokines such as interleukine-6 (IL-6) and tumor necrosis factor-α (TNF-α) and up-regulation of anti-inflammatory cytokines such as IL-10 (Almerighi et al., 2009; Heine et al., 2008). Vitamin D might additionally influence neurodevelopment by regulating calcium through down-regulating the expression of l-type voltage-sensitive calcium channels (Brewer et al., 2001; Gezen-Ak et al., 2011), and up-regulating the expression of calcium binding proteins such as parvalbumin and calbindin in embryonic neurons (Alexianu et al., 1998; Kalueff et al., 2004).

    View all citing articles on Scopus
    View full text