1α,25-Dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in Human Monocytes
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)
Immunomodulatory actions of 1,25-dihydroxyvitamin D3
J Steroid Biochem Mol Biol
(1995)- et al.
1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level
Cytokine
(1992) - et al.
Regulation of human monocyte HLA-DR and CD4 antigen expression, and antigen presentation by 1,25-dihydroxyvitamin D3
Blood
(1990) - et al.
Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor
Blood
(1998) - et al.
Levated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases
J Autoimmun
(2006) - et al.
Monocyte-derived IL12, CD86 (B7–2) and CD40L expression in relapsing and progressive multiple sclerosis
Clin Immunol
(2003) - et al.
A rapid and simple method for measuring tymocyte apoptosis by propidium iodide staining and flow cytometry
J Immunol Meth
(1991) - et al.
Effect of different activation stimuli on the cytokine response of human macrophages to CD40L
Cytokine
(2001) - et al.
Immunomodulatory effects of 1,25-dihydroxyvitamin D3
Curr Opin Nephrol Hypertens
(1995) - et al.
1,25-dihydroxyvitamin D3 receptors in human leukocytes
Science
(1983)
Inhibition of interleukin-1 production by 1,25-dihydroxyvitamin D3
J Clin Endocrinol Metab
1, 25-Dihydroxivitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells
J Clin Invest
Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3
J Clin Invest
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
Vitamin D differentially regulates B7.1 and B7.2 expression on human peripheral blood monocytes
Immunology
Decreased accessory cell function and costimulatory activity by 1,25-dihydroxyvitamin D3-treated monocytes
Arthritis Rheumatol
The role of CD40 and its ligand in the regulation of the immune response
Immunol Rev
The CD40 ligand: at the centre of the immune universe?
Immunol Res
Immune regulation by CD40 and its ligand gp39
Annu Rev Immunol
CD40 and CD154 in cell mediated immunity
Annu Rev Immunol
Cloning of TRAP, a ligand for CD40 on human T cells
Eur J Immunol
CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40
J Exp Med
Stimulation of CD40 with purified soluble gp 39 induces proinflammatory responses in human monocytes
J Immunol
CD40 ligation prevents trypanosoma cruzi infection through interleukin-12 upregulation
Infect Immun
Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes
J Clin Invest
Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment
Autoimmunity
Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis
Clin Exp Immunol
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
Increased T cell expression of CD154 (CD40-ligand) in multiple sclerosis
Eur J Neurol
Plasma levels of soluble CD40 ligand are elevated in inflammatory bowel diseases
Int J Colorectal Dis
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