Wit, H.J. de

TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors (Article)

2011-03-01T00:00:00Z

Abstract INTRODUCTION: Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia. AIM: To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression. METHODS: Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12. CONCLUSION: In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ, BD and MDD.

Monocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk: A study of identical twins (Article)

2010-07-01T00:00:00Z

OBJECTIVE - Monocytes in childhood-onset type 1 diabetes show distinct gene expression. We hypothesize that monocyte activation in monozygotic (MZ) twin pairs discordant for childhood-onset type 1 diabetes could reflect distinct stages of the disease process including diabetes susceptibility (differences between twins, both diabetic and nondiabetic, and control subjects) and/or disease progression (differences between diabetic and nondiabetic twins). RESEARCH DESIGN AND METHODS - We studied patterns of inflammatory gene expression in peripheral blood monocytes of MZ twin pairs (n = 10 pairs) discordant for childhood-onset type 1 diabetes, normal control twin pairs (n = 10 pairs), and healthy control subjects (n = 51) using quantitative-PCR (Q-PCR). We tested the 24 genes previously observed by whole genome analyses and verified by Q-PCR in autoimmune diabetes and performed a hierarchical cluster analysis. RESULTS - Of 24 genes abnormally expressed in childhoodonset type 1 diabetes, we revalidated abnormal expression in 16 of them in diabetic twins including distinct sets of downregulated (P < 0.03) and upregulated (P < 0.02) genes. Of these 16 genes, 13 were abnormally expressed in nondiabetic twins, implicating these genes in diabetes susceptibility (P < 0.044 for all). Cluster analysis of monocyte gene-expression in nondiabetic twins identified two distinct, mutually exclusive clusters, while diabetic twins had a network of positively correlated genes. CONCLUSIONS - Patients with childhood-onset type 1 diabetes show abnormal monocyte gene-expression levels with an altered gene-expression network due to gene-environment interaction. Importantly, perturbed gene-expression clusters were also detected in nondiabetic twins, implicating monocyte abnormalities in susceptibility to diabetes.

An inflammatory gene-expression fingerprint in monocytes of autoimmune thyroid disease patients (Article)

2010-04-01T00:00:00Z

Context: In monocytes of patients with autoimmune diabetes, we recently identified a gene expression fingerprint of two partly overlapping gene clusters, a PDE4B-associated cluster (consisting of 12 core proinflammatory cytokine/compound genes), a FABP5-associated cluster (three core genes), and a set of nine overlapping chemotaxis, adhesion, and cell assembly genes correlating to both PDE4B and FABP5. Objective: Our objective was to study whether a similar monocyte inflammatory fingerprint as found in autoimmune diabetes is present in autoimmune thyroid disease (AITD). Design and Patients: Quantitative PCR was used for analysis of 28 genes in monocytes of 67 AITD patients and 70 healthy controls. The tested 28 genes were the 24 genes previously found abnormally expressed in monocytes of autoimmune diabetes patients plus four extra genes found in whole-genome analysis of monocytes of AITD patients reported here. Results: Monocytes of 24% of AITD and 50% of latent autoimmune diabetes of adults (LADA) patients shared an inflammatory fingerprint consisting of the set of 24 genes of the PDE4B, FABP5, and overlapping gene sets. This study in addition revealed that FCAR, the gene for the Fcα receptor I, and PPBP, the gene for CXCL7, were part of this proinflammatory monocyte fingerprint. Conclusions:Ourstudy providesanimportant tool to determine a shared, specific proinflammatory state of monocytes in AITD and LADA patients, enabling further research into the role of such proinflammatory cells in the failure to preserve tolerance in these conditions and of key fingerprint genes involved. Copyright

Distinct monocyte Gene-Expression profiles in autoimmune diabetes (Article)

2008-10-01T00:00:00Z

OBJECTIVE-There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS-We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) (n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS-We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile - onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS-Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.

Patients with schizophrenia show raised serum levels of the pro-inflammatory chemokine CCL2: Association with the metabolic syndrome in patients? (Letter To Editor)

2008-07-01T00:00:00Z

An imbalance in the production of IL-1β and IL-6 by monocytes of bipolar patients: Restoration by lithium treatment (Article)

2007-11-01T00:00:00Z

Objectives: To study the ex vivo interleukin (IL)-1 β and IL-6 production of monocytes in bipolar disorder (BD) patients in the absence/presence of lithium. Methods: Monocytes of outpatients with DSM-IV BD (n=80, of whom 64 were lithium-treated) and of healthy control subjects (n=59) were cultured in vitro and exposed (24h) or not exposed to lipopolysaccharide (LPS) and/or graded concentrations of lithium chloride (LiCl). IL-1 β and IL-6 production was assessed by enzyme-linked immunosorbent assay (ELISA) (supernatants). Results: Monocytes stimulated by LPS from non-lithium-treated bipolar patients were characterized by an abnormal IL-1 β/IL-6 production ratio, i.e., low IL-1 β and high IL-6 production. Lithium treatment increased IL-1 β and decreased IL-6 production and thus restored the aberrant ratio. In vitro exposure of monocytes to LiCl did not have the same effects as lithium treatment: the procedure decreased IL-1 β production and had minimal effects on IL-6 production. Conclusion: Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.

1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes (Article)

2001-01-01T00:00:00Z

Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells (Article)

2000-01-01T00:00:00Z

BACKGROUND: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. AIM: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (10 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. RESULTS: The continuous presence of DHEA (10 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity). The continuous presence of DEX at a concentration of 10 M in the monocyte/DC cultures resulted in the generation of plastic-adherent macrophage-like cells in place of typical immature DC, with increased CD14 expression, but decreased expression of the typical DC markers CD1a, CD40 and CD80. These cells were strongly reactive to acid phosphatase, but equally capable of stimulating T cell proliferation as immature DC. The production of IL-12 by these macrophage-like cells was virtually shut down, whereas the production of IL-10 was significantly higher than that of control immature DC. CONCLUSION: The continuous presence of a high level of GC during the generation of immature DC from monocytes can modulate this development away from DC towards a macrophage-like cell. The combination of a low CD80 expression and a shutdown of IL-12 production suggests the possibility of DEX-generated cells initiating a Th2-biased response. These effects by DEX on DC development contrast with those by DHEA, which resulted in a more typical DC although possessing a phenotype possibly indicating a more mature state of the cell.