Experimental Biology 2010: Relative Pro-Atherogenic Impact Of Omalizumab Versus Celecoxib On Cholesterol Transport Proteins In THP-1 Human Monocytes

Purpose of Study: The cyclooxygenase (COX)-2 inhibitor, celecoxib is an anti-inflammatory and analgesic, while omalizumab, a humanized monoclonal anti-IgE antibody is used to treat allergic asthma. Published studies indicate that celecoxib and possibly omalizumab increase risk of myocardial infarction and stroke. We previously reported that COX-2 inhibitors reduce expression of the anti-atherogenic reverse cholesterol transport (RCT) proteins, cholesterol 27-hydroxylase (27-OHase) and ATP binding cassette transporter A1 (ABCA1). These proteins are crucial for efficient cholesterol efflux, a process that prevents foam cell formation and protects against atherosclerosis. In this study, we investigated the effect of omalizumab on expression of these RCT proteins as well as on scavenger receptor CD36 (promotes cholesterol influx) in THP-1 human monocytes and compared its effect to celecoxib.

Methods Used: THP-1 human monocytes (10^6cells/ml), an established model of atherosclerosis, were incubated (20 hrs, 37°C, 5% CO2) ± omalizumab (500 µg/ml and 1000 µg/ml), ± celecoxib (50µM) and ± the atherogenic cytokine interferon (IFN)-? (500 U/mL). Expression of ABCA1, 27-OHase and CD36 message was evaluated by quantitative real-time PCR. Studies were performed in triplicate.

Summary of Results: In cultured THP-1 monocytes, omalizumab had a modest impact on ABCA1 and 27-OHase mRNA, but had no effect on the expression of CD36 mRNA, while celecoxib significantly changed expression of each of these proteins in an atherogenic manner. Following celecoxib exposure, 27-OHase and ABCA1 mRNAs decreased by 77.9.±10.38% and 64.8±8.55%, respectively while CD36 increased by 37.5±3.91% (100% = baseline expression in untreated THP-1). Omalizumab treatment of THP-1 monocytes (1000 µg/ml) decreased message for the 27-OHase and ABCA1 by 28.6±3.77% and 27.6±3.68%, respectively, while CD36 expression did not change significantly.

Conclusions: COX-2 inhibition may contribute to the pathological process of atherosclerosis by promoting lipid overload through effects on genes involved in cholesterol transport, while omalizumab does not substantially affect these pathways. If reported cardiovascular and cerebrovascular risks are confirmed with omalizumab, the effect is likely by an alternate mechanism.