Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure.
OBJECTIVE
Inflammation may play a pathogenic role in chronic heart failure (CHF). The objective of the study was to characterise the imbalance in the cytokine network in CHF.


METHODS
cDNA expression arrays were used to analyse the gene expression of cytokines and related mediators in peripheral blood mononuclear cells (PBMC) from CHF patients (n=8) and healthy controls (n=8). Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of individual genes in additional 12 patients and eight controls.


RESULTS
From 375 genes, 34 were upregulated and two downregulated in CHF patients in the cDNA expression array experiments. Regulated genes included chemokines/-receptors, members of the transforming growth factor beta superfamily, orphan receptors and in particular several members of the tumor necrosis factor (TNF) superfamily. Thus, 4-1BB ligand (L), APRIL, CD27L, CD40L, FasL, LIGHT, TRAIL-receptor 4 were upregulated, while TRAIL-receptor 3 was downregulated. Real-time quantitative RT-PCR confirmed significantly upregulated gene expression of APRIL, LIGHT, FasL and CD27L in CHF patients and showed in addition significantly enhanced gene expression of TNFalpha and TRAIL.


CONCLUSIONS
The present study demonstrates differential gene expression in PBMC of several members of the cytokine network in CHF. In particular, the enhanced expression of several ligands in the TNF superfamily may reflect a potential pathogenic role of these cytokines in CHF.
Yndestad
Arne
A
Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Norway. arne.yndestad@klinmed.uio.no
Damås
Jan Kristian
JK
Geir Eiken
Hans
H
Holm
Torbjørn
T
Haug
Terje
T
Simonsen
Svein
S
Frøland
Stig S
SS
Gullestad
Lars
L
Aukrust
Pål
P
D053330:4-1BB Ligand; D000368:Aged; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D053282:CD27 Ligand; D023201:CD40 Ligand / Q000235:genetics; D016022:Case-Control Studies; D053222:Fas Ligand Protein; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D053330:4-1BB Ligand; C490341:ANP32B protein, human; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D053282:CD27 Ligand; C505771:CD70 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; C505914:TNFSF14 protein, human; C505974:TNFSF9 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand