Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells.
OBJECTIVE
To compare the global effects of oxidized LDL (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) on gene expression in human monocytic cells and to identify differentially expressed genes involved with inflammation and survival.


RESULTS
U937 cells were treated with oxLDL-IC, oxLDL, Keyhole limpet hemocyanin immune complexes (KLH-IC), or vehicle for 4h. Transcriptome profiling was performed using DNA microarrays. oxLDL-IC uniquely affected the expression of genes involved with pro-survival (RAD54B, RUFY3, SNRPB2, and ZBTB24). oxLDL-IC also regulated many genes in a manner similar to KLH-IC. Functional categorization of these genes revealed that 39% are involved with stress responses, including the unfolded protein response which impacts cell survival, 19% with regulation of transcription, 10% with endocytosis and intracellular transport of protein and lipid, and 16% with inflammatory responses including regulation of I-kappaB /NF-kappaB cascade and cytokine activity. One gene in particular, HSPA6, greatly up-regulated by oxLDL-IC, was found to be required for the process by which oxLDL-IC augments IL1-beta secretion. The study also revealed genes uniquely up-regulated by oxLDL, including genes involved with growth inhibition (OKL38, NEK3, and FTH1), oxidoreductase activity (SPXN1 and HMOX1), and transport of amino acids and fatty acids (SLC7A11 and ADFP).


CONCLUSIONS
These findings highlight early transcriptional responses elicited by oxLDL-IC that may underlie its cytoprotective and pro-inflammatory effects. Cross-linking of Fc gamma receptors appears to be the trigger for most of the transcriptional responses to oxLDL-IC. The findings further strengthen the hypothesis that oxLDL and oxLDL-IC elicit disparate inflammatory responses and play distinct roles in the process of atherosclerosis.
Hammad
Samar M
SM
Department of Cell Biology and Anatomy, Medical University of South Carolina, 114 Doughty Street, 630B, P.O. Box 250776, Charleston, SC 29425, USA. hammadsm@musc.edu
Twal
Waleed O
WO
Barth
Jeremy L
JL
Smith
Kent J
KJ
Saad
Antonio F
AF
Virella
Gabriel
G
Argraves
W Scott
WS
Lopes-Virella
Maria F
MF
D000936:Antigen-Antibody Complex / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D005487:Foam Cells / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006433:Hemocyanins / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011973:Receptors, LDL / Q000235:genetics; D020298:U937 Cells
D000936:Antigen-Antibody Complex; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin