Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Atherogenic Effect of Inflammatory Cytokines in Chronic Inflammatory Diseases.
Hashizume, Misato, Mihara, Masahiko
In patients with chronic inflammatory diseases such as rheumatoid arthritis (RA), the risk of cardiovascular disease (CVD) is increased. Inflammatory cytokines are considered of fundamental importance to atherogenesis. It was reported that high level scavenger receptor-A (SR-A) gene expression is associated with an increased incidence of cardiovascular events in acute coronary syndrome. SR-A is expressed on macrophages and facilitates the intracellular accumulation of oxidized LDL (oxLDL), resulting in the formation of atherosclerotic plaque. To explore whether inflammatory cytokines promote atherogenesis, we examined their effects on SR-A expression oxLDL accumulation.
THP-1 cells were induced to differentiate into macrophage-like cells (THP-1/macrophages) by culture with phorbol myristate acetate for 4 days. THP-1/macrophages were then stimulated for 24 h by serum from RA patients or healthy subjects, and IL-6 and TNF-a in the presence or absence of anti-IL-6 receptor antibody (tocilizumab, TCZ) or TNF-a receptor (p75)-Fc (etanercept, ETN). The level of SR-A mRNA was measured by real-time PCR. Cells were further incubated with oxLDL for a specific time. Intracellular accumulation of oxLDL was measured by Oil Red O staining and fluorescence.
First, we determined the effect of TNF-a and IL-6 on the expression of SR-A and formation of atherosclerotic plaque. Either cytokine induced SR-A mRNA expression and increased intracellular oxLDL accumulation by THP-1/macrophages. ETN inhibited the induction of SR-A by TNF-a. Interestingly, TCZ inhibited SR-A induction by IL-6 as well as TNF-a because IL-6 induced by TNF-a increased SR-A expression. To test whether SR-A expression and the accumulation of oxLDL were induced by blood, THP-1/macrophages were cultured in the presence of serum from healthy subjects or RA patients. Serum from the latter but not the former induced expression of SR-A. Moreover, RA patients' serum augmented the accumulation of oxLDL by THP-1/macrophages. Finally, in order to examine the effect of TNF-a and IL-6 on the induction of SR-A expression and the accumulation of oxLDL by RA serum, the sera were incubated with ETN or TCZ. Both agents were found to partially or completely inhibit the induction of SR-A expression and the accumulation of oxLDL stimulated by RA serum.
Inflammatory cytokines, TNF-a and IL-6 induce the expression of SR-A and accumulation of oxLDL. These cytokines are directly implicated in atherosclerotic plaque formation and progression. Our findings indicate that blockade of TNF-a and IL-6 has therapeutic potential for reducing CVD in chronic inflammatory diseases. We are now examining the expression of SR-A and plaque formation using macrophages from patients with chronic inflammatory diseases.
To cite this abstract, please use the following information:
Hashizume, Misato, Mihara, Masahiko; Atherogenic Effect of Inflammatory Cytokines in Chronic Inflammatory Diseases. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1838