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Altered AKT1 and MAPK1 gene expression on peripheral blood mononuclear cells and correlation with T-helper-transcription factors in systemic lupus erythematosus patients.

ABSTRACT: Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin). Age- and gender-matched thirteen healthy controls were examined. AKT1 and MAPK1 expressions were upregulated in SLE patients and correlated with Th17-(Retinoic acid-related orphan receptor (ROR)-C), T-regulatory-(Treg)-(Transforming Growth Factor Beta (TGFB)-2), and Th2-(interleukin (IL)-5)-related genes. MAPK1 expression correlated with Th1-(IL-12A, T-box TF-(T-bet)), Th2-(GATA binding protein-(GATA)-3), and IL-10 expressions. IL-10 expression was increased and correlated with plasma Tumor Necrosis Factor (TNF)-? and Th0-(IL-2), Th1-(IL-12A, T-bet), GATA3, Treg-(Forkhead/winged-helix transcription factor- (FOXP)-3), and IL-6 expressions. FOXP3 expression, FOXP3/RORC, and FOXP3/GATA3 expression ratios were increased. Plasma IL-1?, IL-12(p70), Interferon-(IFN)-?, and IL-6 cytokines were augmented. Plasma IL-1?, IL-6, IL-2, IFN-?, TNF-?, IL-10, and IL-13 correlated with C-reactive protein, respectively. Increased Calprotectin correlated with neutrophils. Conclusion, SLE patients presented a systemic immunoinflammatory activity, augmented AKT1 and MAPK1 expressions, proinflammatory cytokines, and Calprotectin, together with increased expression of Treg-related genes, suggesting a regulatory feedback opposing the inflammatory activity.

SUBMITTER: Garcia-Rodriguez S

PROVIDER: S-EPMC3483815 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Altered AKT1 and MAPK1 gene expression on peripheral blood mononuclear cells and correlation with T-helper-transcription factors in systemic lupus erythematosus patients.

Garcia-Rodriguez Sonia S Callejas-Rubio Jose-Luis JL Ortego-Centeno Norberto N Zumaquero Esther E Ríos-Fernandez Raquel R Arias-Santiago Salvador S Navarro Pilar P Sancho Jaime J Zubiaur Mercedes M

Mediators of inflammation 20121018

Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene ...[more]

PMID: 23125486

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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease with a complicated pathogenesis, and its aetiology has not been clearly unveiled. The lack of effective diagnosis and treatment methods makes it necessary to explore the molecular mechanism of SLE. We aimed to identify some critical signalling pathways and key competing endogenous RNAs (ceRNAs) underlying the molecular mechanism of SLE and to map out the systematic signalling networks by integrating the data on different kinds of RNAs.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from both SLE patients and healthy subjects, RNA was extracted from the PBMCs, and RNA libraries including ribosomal RNA-depleted strand-specific libraries and small RNA libraries were built for deep RNA sequencing (RNA-seq). RNA-seq yielded differential expression profiles of lncRNAs/circRNAs/miRNAs/mRNAs related to SLE. The DAVID database (v. 6.8) was employed for Gene Ontology (GO) and KEGG pathway analysis. ceRNA networks (circRNA/lncRNA-miRNA-mRNA) were constructed and visualized using Cytoscape software (v. 3.5.0). The TargetScan and miRanda databases were used to predict target relationships in ceRNA networks. qRT-PCR was used to verify our data.ResultsDifferential expression of ceRNAs related to SLE was detected in SLE patients' PBMCs: 644 mRNAs (384 upregulated, 260 downregulated), 326 miRNAs (223 upregulated, 103 downregulated), 221 lncRNAs (79 upregulated, 142 downregulated), and 31 circRNAs (21 upregulated, 10 downregulated). We drew ceRNA signalling networks made up of the differentially expressed mRNAs/miRNAs/lncRNAs/circRNAs mentioned above, and the hub genes included IRF5, IFNAR2, TLR7, IRAK4, STAT1, STAT2, C2, and Tyk2. These hub genes were involved in ceRNA signalling pathways, such as the IL-17 signalling pathway and type I interferon signalling pathway.ConclusionsWe explored the differential expression profiles of various kinds of ceRNAs and integrated signalling networks constructed by ceRNAs. Our findings offer new insights into the pathogenesis of SLE and hint at therapeutic strategies.

Project description:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by overactive inflammation and aberrant activation of lymphocytes. Chemokine C-X-C motif ligand 10 (CXCL10) has an important role in the initiation and deterioration of SLE. However, the expression levels of CXCL10 mRNA in T-helper (Th) cells and B lymphocytes from SLE patients have remained elusive. In the present study, a Bioinformatics analysis of differentially expressed gene (DEG) profiles obtained from RNA sequencing data for three matched samples was performed to explore the hub genes, mainly through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction analysis. Furthermore, the expression of CXCL10 in peripheral blood mononuclear cells (PBMCs), CD4+ Th cells and CD19+ B cells of 108 subjects, including 66 SLE patients and 42 healthy controls, was confirmed by reverse transcription-quantitative PCR. In addition, 4 single-nucleotide polymorphism (SNP) loci in the 3'-untranslated region of CXCL10 were assessed using the Snapshot SNP genotyping assay. A total of 152 clustered DEGs mainly accumulated in immune-associated GO terms and interferon-associated pathways were identified. The expression of CXCL10, one of the central genes in the interaction network cluster (the degree of interaction, MCODE score=28.414), was 6.27-fold higher in SLE patients compared with control patients. Furthermore, CXCL10 mRNA was confirmed to be elevated in PBMCs and CD19+ B cells of patients with SLE (P<0.001 for the two cell types). However, no significant difference in CD4+ T lymphocytes was present (P=0.881). In addition, no polymorphism was identified in four selected loci from the samples. Taken together, the present results demonstrated that CXCL10, one of the hub genes in the pathogenesis of SLE, is upregulated in PBMCs and B lymphocytes of patients with SLE, although none of the SNPs selected for analysis in the present study were identified to have any potential associations with SLE.

Project description:Introduction: The role of the immune response in the pathogenesis of antiphospholipid syndrome (APS) remains elusive. It is possible that differences in the frequencies of Th17 cells and/or defects in the immunoregulatory mechanisms are involved in the pathogenesis of APS. Our aim was to determine the peripheral blood Th cells phenotype and the circulating cytokine profile in patients with primary APS (pAPS) and compare it with systemic lupus erythemathosus (SLE) as disease control group. Methods: The frequencies of circulating regulatory T cells (Tregs) were determined in PBMCs from 36 patients with pAPS by flow cytometry. As control groups we included 21 age- and gender-matched healthy controls (HC) and 11 patients with SLE. The suppressive capacity of Tregs was evaluated in vitro by coculture assay. On the other hand, intracellular cytokine production was assessed in Th1, Th2, and Th17 cells and circulating IL-6, IL-10, and IL-35 were measured by Cytometric Bead Array and ELISA. The quantification of Th master gene expression levels was performed by real time quantitative PCR. Results: pAPS patients and SLE patients did not show differences in the percentage or number of Tregs compared to HC. The suppressive capacity of Tregs was also similar in the three study group. Instead, we found higher FoxP3·mRNA expression levels in pAPS patients and HC than SLE patients. Regarding the Th17 response, patients with pAPS and HC showed a significantly lower frequency of circulating Th17 cells than SLE. However, no differences were observed in the Th1 response between patients and controls. Thus, increased Th17/Th1 and Th17/Treg ratios were found in SLE patients but not in pAPS patients. pAPS and SLE patients had higher serum IL-6 levels than HC but there was not difference between both disease groups. Besides, a significant increase in the immunosuppressive cytokine levels was observed only in pAPS as compared to HC. Conclusions: Our data demonstrate an increased inflammatory profile of peripheral blood CD4+ T cells from SLE as compared with pAPS mostly due to an increased Th17 response. In conclusion, there seems not to be a direct pathogenic role for Th cells in pAPS but in SLE.

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Altered AKT1 and MAPK1 gene expression on peripheral blood mononuclear cells and correlation with T-helper-transcription factors in systemic lupus erythematosus patients.

Publications

Altered AKT1 and MAPK1 gene expression on peripheral blood mononuclear cells and correlation with T-helper-transcription factors in systemic lupus erythematosus patients.

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