The anaphylatoxin C5a is a potent mediator of innate immunity and promotes inflammation via its receptor C5aR1 upon complement system activation danger-associated molecular patterns. Both C5a and C5aR1 are thought to be contributing factors in inflammatory and infectious conditions of the bone. Bone fracture healing, for example, was significantly improved when applying a C5aR1-antagonist in a rodent model of severe systemic inflammation and osteoblasts were found to be target cells for C5a in this setting. Interestingly, osteoblasts up-regulate C5aR1 during osteogenic differentiation and after bone injury. Further, C5a induces inflammatory cytokines, such as IL-6, and the osteoclastogenic mediator RANKL in osteoblasts. However, the molecular mechanisms underlying C5a-C5aR1 signaling axis in osteoblasts remain unclear, and further targets of C5a are still elusive. Using microarray analysis, we analyzed intracellular events following C5aR1 activation in osteoblasts and defined up- or down-regulated genes and their belonging biological pathways.
C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast-inducing chemokine CXCL10.
Treatment
View SamplesPancreatic islets are central in type 2-diabetes development, which coincides with increased activity of innate immunity. Intriguingly, human pancreatic islets express many complement genes. The most highly expressed gene was the complement inhibitor CD59 that is GPI anchored to the cell membrane, which unexpectedly was found in high amounts intracellularly in beta cells. Silencing of CD59 strongly suppressed insulin secretion. Importantly, this suppression was unrelated to established CD59 functions, but rather depletion of intracellular CD59. Imaging experiments identified a distal site of inhibition in the exocytotic pathway, but prior to emptying of the insulin granules. Proximity Ligation Assays pin-pointed the mechanism to impaired turnover of exocytosis-regulating SNARE-proteins and CD59 was detected in complex with VAMP2 and syntaxin. CD59 was downregulated by 24-h glucose incubations in human islets, rat cell lines and in islets from three rodent diabetes models.
The complement inhibitor CD59 regulates insulin secretion by modulating exocytotic events.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
TCF7L2 is a master regulator of insulin production and processing.
Sex, Age, Specimen part
View SamplesHere we harnessed the potential of expression arrays in 89 human pancreatic islet donors (different levels of blood glucose (HbA1c)) to identify genes regulated in this relevant tissue for type 2 diabetes (T2D).
TCF7L2 is a master regulator of insulin production and processing.
Sex, Age, Specimen part
View SamplesClose to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability.
A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets.
Sex, Age, Specimen part
View SamplesA goal of this study was to identify and investigate previously unrecognized components of the remodeling process in the progression to heart failure by comparing gene expression in ischemic, failing (F) to non-failing (NF) hearts. These results also were compared to the changes observed in a proteomic analysis of F and NF hearts.
Differential protein expression and basal lamina remodeling in human heart failure.
Specimen part
View SamplesFour male SHR/Ola, BN and SHR-18 rats were fed a normal diet and sacrificed at 9 weeks of age. Four male SHR/Ola and SHR-18 rats at 8 weeks of age were fed 1% NaCl for one week and then sacrificed. Kidneys were removed and frozen in liquid nitrogen for all 20 animals. Total RNA was isolated, labelled cRNA was generated and hybridised to Affymetrix Rat RG-U34ABC arrays.
Dissection of chromosome 18 blood pressure and salt-sensitivity quantitative trait loci in the spontaneously hypertensive rat.
Sex, Age, Specimen part
View SamplesRight ventricular failure was induced thourgh pulmonary banding in 11 pigs. Right ventricular failure was defined as a SRVP >50 mmHg during two hours. After right ventricular failure was induced, half the pigs were treated with a Glenn-shunt combined with pulmonary banding for one hour, and the other half served as control group with pulmonary banding only. The aim was to study the change in global gene expression during right ventricular failure due to pulmonary banding, and the effect of volume unloading during pulmonary banding.
A modified Glenn shunt reduces venous congestion during acute right ventricular failure due to pulmonary banding: a randomized experimental study.
Specimen part, Treatment
View SamplesIn this study, we use pre-malignant cells from different Cebpa mutant acute myeloid leukemia (AML) models. We have used conditional KO models (CreLoxP) and isolated hematopoietic cells shortly after induction of recombination, in order to look at pre-leukemic cells, which have acquired the first hit, but not yet undergone full malignant transformation.
Lack of the p42 form of C/EBPα leads to spontaneous immortalization and lineage infidelity of committed myeloid progenitors.
Sex, Specimen part
View SamplesTo identify factors and pathways regulated by IMP proteins and obtain leads to the mechanism behind the phenotypic changes, we compared the gene expression profiles of IMP siRNA treated cells with mock treated cells. Triplicate gene expression profiles were generated from both the IMP(1,3)A and IMP(1,3)B siRNA sets and were compared to the mock transfected cells. cRNA was hybridized to Affymetrix human U133A arrays.
RNA-binding IMPs promote cell adhesion and invadopodia formation.
Specimen part, Cell line
View Samples