Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of rat chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h to investigate TNF-a-induced MEK/ERK-dependent regulation of Cartilage Matrix Genes

ABSTRACT: TNF-a is increased in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. TNF-a activates MEK/ERK in chondrocytes; however the overall functional relevance of MEK/ERK to TNF-a-regulated gene expression in chondrocytes is unknown. Chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h. Microarray analysis was used to identify genes regulated by TNF-a in a MEK1/2-dependent fashion. Experiment Overall Design: Primary chondrocytes from the femoral condyles of neonatal rats were treated with DMSO (control sample), TNF-a, U0126 (selective MEK1/2 inhibitor) or TNF-a and U0126. Two biological replicates were collected for each treatment. Total RNA was collected and analyzed by Affymetrix Microarray.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Jason Scott Rockel

PROVIDER: E-GEOD-14402 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Identification of MEK-ERK or p38MAPK dependent genes in human monocyte derived dendritic cells. Dendritic cells (DC) promote tolerance or immunity depending on their maturation state. Previous studies have revealed that DC maturation is enhanced or accelerated upon MEK-ERK signaling pathway inhibition. We have now determined the contribution of MEK-ERK activation to the profile of gene expression of human immature monocyte-derived dendritic cells (MDDC) and peripheral blood myeloid DC. ERK inhibition altered the expression of genes that mediate CCL19-directed migration (CCR7) and LDL binding (CD36, SCARB1, OLR1, CXCL16) by immature DC. Besides, ERK upregulated CCL2 expression while impaired the expression of DC maturation markers (RUNX3, ITGB7, IDO1). MEK-ERK-regulated genes exhibited an over-representation of cognate sequences for the Aryl Hydrocarbon Receptor (AhR) transcription factor, and we show that AhR mediates some of the ERK-dependent transcriptional effects in DC. Therefore, MEK-ERK signaling pathway regulates antigen capture, lymph node homing and the acquisition of maturation-associated genes, and its contribution to the maintenance of the immature state of MDDC and myeloid DC is partly dependent on the activity of AhR. Since pharmacological modulation of the MEK-ERK signaling pathway has been proposed as a potential therapeutic strategy for cancer, our findings indicate that ERK inhibitors might influence the generation of anti-tumor responses through regulation of critical DC effector functions. Human peripheral blood monocytes from three independent healthy donors (DC4, DC5 and DC7) were isolated by anti-CD14-labeled magnetic microbeads. CD14+ monocytes were cultured for 5 days in RPMI 10% FCS containing GM-CSF and IL-4 to generate immature monocyte-derived dendritic cells (MDDC). Immature MDDC were exposed to MEK inhibitor, U0126, or p38MAPK inhibitor, SB203580 for 1 hour and a final dose of GM-CSF and IL-4 were added to the culture. Cells were collected for analysis after 4, 10 or 24 hours.Total RNA from each condition was extracted using the All prep DNA/RNA/protein mini kit (Qiagen) and hybridized to an Agilent Human Whole Genome (4x44) Oligo Microarray. All experimental procedures were performed following manufacturer instructions.

Dataset Information

Transcription profiling of rat chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h to investigate TNF-a-induced MEK/ERK-dependent regulation of Cartilage Matrix Genes

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