Insight in modulation of inflammation in response to diclofenac intervention: a human intervention study.
BACKGROUND
Chronic systemic low-grade inflammation in obese subjects is associated with health complications including cardiovascular diseases, insulin resistance and diabetes. Reducing inflammatory responses may reduce these risks. However, available markers of inflammatory status inadequately describe the complexity of metabolic responses to mild anti-inflammatory therapy.


METHODS
To address this limitation, we used an integrative omics approach to characterize modulation of inflammation in overweight men during an intervention with the non-steroidal anti-inflammatory drug diclofenac. Measured parameters included 80 plasma proteins, >300 plasma metabolites (lipids, free fatty acids, oxylipids and polar compounds) and an array of peripheral blood mononuclear cells (PBMC) gene expression products. These measures were submitted to multivariate and correlation analysis and were used for construction of biological response networks.


RESULTS
A panel of genes, proteins and metabolites, including PGE2 and TNF-alpha, were identified that describe a diclofenac-response network (68 genes in PBMC, 1 plasma protein and 4 plasma metabolites). Novel candidate markers of inflammatory modulation included PBMC expression of annexin A1 and caspase 8, and the arachidonic acid metabolite 5,6-DHET.


CONCLUSIONS
In this study the integrated analysis of a wide range of parameters allowed the development of a network of markers responding to inflammatory modulation, thereby providing insight into the complex process of inflammation and ways to assess changes in inflammatory status associated with obesity.


BACKGROUND
The study is registered as NCT00221052 in clinicaltrials.gov database.
van Erk
Marjan J
MJ
TNO Quality of Life, PO Box 360, 3700 AJ Zeist, the Netherlands. marjan.vanerk@tno.nl
Wopereis
Suzan
S
Rubingh
Carina
C
van Vliet
Trinette
T
Verheij
Elwin
E
Cnubben
Nicole H P
NH
Pedersen
Theresa L
TL
Newman
John W
JW
Smilde
Age K
AK
van der Greef
Jan
J
Hendriks
Henk F J
HF
van Ommen
Ben
B
D000328:Adult; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015992:Body Mass Index; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D004008:Diclofenac / Q000627:therapeutic use*; D015232:Dinoprostone / Q000097:blood; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D050177:Overweight; D040901:Proteomics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D017305:Annexin A1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D053181:Caspase 8; D015232:Dinoprostone