High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2

Atherogenesis is a multifactorial chronic inflammatory disease in which low plasma levels of HDLs are a strong predictor of the condition. Although th e mechanism of protection by HDLs is not precisely known, HDLs have been sh own to influence many of the events involved in the development of atherosc lerosis. Previously we have shown that HDLs inhibited the cytokine-induced expression of adhesion molecules (E-selectin, VCAM-1, and ICAM-1) by endoth elial cells (ECs). As the complete transcriptional regulation of all 3 gene s requires the NF-kappa B family of transcription factors, we examined the effect of HDLs on activation of NF-kappa B. We also investigated the effect of HDLs on 2 other cytokine-induced genes, granulocyte-macrophage colony-s timulating factor (GM-CSF) and cyclooxygenase (Cox-2; prostaglandin H-2 syn thase, EC 0.1.14.99.1). E-selectin expression in response to tumor necrosis factor-alpha (TNF alpha) was, as expected, inhibited in ECs that had been preincubated with HDLs. However, the level of secretion of GM-CSF in the sa me cultures was no different from control. In a similar manner, although HD Ls had no effect on steady-state mRNA levels of GM-CSF,the levels of E-sele ctin were significantly inhibited by HDLs. In transient cotransfection expe riments we found that HDLs inhibited the cytokine-induced expression of a r eporter gene driven by the E-selectin proximal promoter (-383 to 80) but ha d no effect on the expression of a reporter gene driven under the control o f the proximal promoter of GM-CSF (-627 to 28). As would be predicted from this differential response, HDLs did not influence the nuclear translocatio n or DNA binding of NF-kappa B, or alter the kinetics of degradation and re synthesis of the inhibitory protein I kappa B alpha. We found that HDLs syn ergized with cytokine to enhance the expression of Cox-2 and induce the syn thesis of its main EC product, prostacyclin (PGI(2)), a potent inhibitor of platelet and leukocyte functions, In conclusion, HDL induces an antiinflam matory phenotype in cytokine-induced ECs, synergizing with cytokine to indu ce elevation of Cox-2 in addition to inhibiting adhesion molecule expressio n. Our studies show that these differential effects are mediated in a manne r that is likely to be independent of NF-kappa B per se.