Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients.

Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment.

Monocyte gene-expression profiles associated with childhood-onset type 1 diabetes and disease risk: a study of identical twins.

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 childhood-onset 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.

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 Fcalpha receptor I, and PPBP, the gene for CXCL7, were part of this proinflammatory monocyte fingerprint. CONCLUSIONS: Our study provides an important 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.

The FOXF2 pathway in the human prostate stroma.

BACKGROUND: Forkhead box 2 (FOXF2) is a member of the large family of forkhead transcription factors and its expression pattern suggests a role in prostate cancer development. FOXF2 expression is stroma-specific and higher expressed in the prostate transition zone than the prostate peripheral zone. Moreover, expression of FOXF2 is decreased in prostate cancer. METHODS: To identify the genes and pathways regulated by FOXF2, we compared microarray expression profiles of primary prostate stromal cells (PrSC) treated with control or small interfering RNA (siRNA) directed against FOXF2. RESULTS: From our microarray analyses, we selected 190 differentially expressed genes, of which 104 genes were higher expressed in PrSC cells treated with FOXF2 siRNA and 86 were higher expressed in PrSC cells treated with negative control siRNA. Eight of the strongest differentially expressed genes were validated by RT-PCR. Genes down-regulated by FOXF2 included MT1E, MT1F, PDGFA, ITGB1, and PSG7 and genes up-regulated by FOXF2 included WASF2, BAMBI, and CXCL12. Ingenuity pathway analysis showed several pathways significantly regulated by FOXF2, including PPAR signaling, PDGF signaling, and extracellular matrix (ECM) signaling. GSEA analysis revealed that FOXF2 up-regulated genes were down-regulated in the same PrSC cells treated with transforming growth factor 3 (TGFbeta3). CONCLUSIONS: The distinct expression pattern of FOXF2 in the prostate, its effect on expression of ECM signaling, and its opposing role in the TGFbeta3 pathway, suggests a role for FOXF2 in prostate homeostasis and stroma-epithelial interactions.

Gene expression of forkhead transcription factors in the normal and diseased human prostate.

OBJECTIVE To assess the expression of forkhead transcription factors (FOX) in normal prostate and prostate diseases, as since the first FOX was identified, its family members have been implicated in a variety of cellular processes, including embryonic development and disease. MATERIAL AND METHODS We analysed a set of 12 different FOX genes by quantitative reverse transcription-polymerase chain reaction in prostate zones, prostate cancer, lymph node metastases, benign prostatic hyperplasia (BPH), xenografts and several prostate cell lines. RESULTS There were striking differences among the expression of various FOX family members; most prominent were the high expression of FOXF1 and FOXF2 in the normal prostate transition zone and BPH, and their decreased expression in prostate cancer. Interestingly, although the FOXF genes are stroma-specific, some of the androgen-independent prostate cancer xenografts uniquely express these two genes. FOXD1 and FOXD2 were more highly expressed in prostate cancer and lymph node metastases. FOXA1 and FOXC1 have an opposite expression pattern for androgen-dependent growth of prostate cancer cell lines and xenografts. CONCLUSIONS Various members of the FOX family are differentially expressed in the zones of the normal prostate and in benign and malignant outgrowths. The expression profiles of FOXF1 and FOXF2 suggest a role in epithelial to mesenchymal transition, while FOXA1 and FOXC1 expression is linked to androgen-associated growth status of cancer.

Gene expression profiling of the human prostate zones.

OBJECTIVE: To investigate differences in gene expression in different zones of the prostate by microarray analyses, to better understand why aggressive tumours predominantly occur in the peripheral zone (PZ), whereas benign prostatic hyperplasia (BPH) occurs almost exclusively in the transition zone (TZ). MATERIALS AND METHODS: Expression profiling of both prostate zones was done by microarray analysis. Reverse transcription-polymerase chain reaction (RT-PCR) of the top 18 genes confirmed the microarray analyses. RT-PCR with common cell-type markers indicated that the differential expression between the zones was not caused by an unequal distribution of different cell types. Primary stromal and epithelial prostate cells were used to study cell type expression in the 12 highest differentially expressed zonal-specific genes. RESULTS: In all, 346 genes were identified as preferentially expressed in the TZ or PZ. A few of the TZ-specific genes, including ASPA, FLJ10970 and COCH, were also stroma-specific. Comparisons with other microarray studies showed that gene expression profiles of prostate cancer and BPH correlate with the expression profiles of the PZ and TZ, respectively. CONCLUSION: Gene expression differs between the PZ and TZ of the prostate, and stromal-epithelial interactions might be responsible for the distinct zonal localization of prostate diseases.