Proinflammatory cytokines regulate LOX-1 expression in vascular smooth muscle cells.
OBJECTIVE
Atherogenesis represents a type of chronic inflammation and involves elements of the immune response, eg, the expression of proinflammatory cytokines. In advanced atherosclerotic lesions, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs). In vitro, the expression of LOX-1 is induced by inflammatory cytokines like TNF-alpha and transforming growth factor (TGF)-beta. Therefore, LOX-1 is thought to be upregulated locally in response to cytokines in vivo.


RESULTS
We determined by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis whether the mediators of the acute phase response in inflammation, IL-1alpha, IL-1beta, and TNF-alpha, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor gamma (PPARgamma). We studied by immunohistochemistry whether these cytokines are spatially correlated with LOX-1 expression in advanced atherosclerotic lesions. We found upregulation of LOX-1 expression in SMC in a dose- and time-dependent manner after incubation with IL-1alpha, IL-1beta, and TNF-alpha. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPARgamma activator, 15d-PGJ(2), however, inhibited IL-1beta-induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1alpha, IL-1beta, and TNF-alpha expression corresponded to regions of LOX-1 expression.


CONCLUSIONS
We suppose that upregulated LOX-1 expression in SMC of advanced atherosclerotic lesions is a response to these proinflammatory cytokines. Moreover, the proinflammatory effects of these cytokines can be decreased by the antiinflammatory effect of PPARgamma.
Institute for Arteriosclerosis Research, University of Muenster, Germany. hofnagel@uni-muenster.de
Oliver
O
Hofnagel
Birgit
B
Luechtenborg
Katrin
K
Stolle
Stefan
S
Lorkowski
Heike
H
Eschert
Gabriele
G
Plenz
Horst
H
Robenek
D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007834:Lasers; D042282:Microdissection / Q000379:methods; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000096:biosynthesis*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017539:Tunica Intima / Q000166:cytology; D017540:Tunica Media / Q000166:cytology
C477819:15-deoxyprostaglandin J2; D016207:Cytokines; D007375:Interleukin-1; C495137:OLR1 protein, human; D047495:PPAR gamma; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D014409:Tumor Necrosis Factor-alpha; D015230:Prostaglandin D2