Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806518

Received for publication August 16, 2006.

Accepted for publication October 2, 2006.

Article

The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis

Yankun Li and Ira Tabas @

Department of Medicine, Columbia University, New York, New York, USA

@ To whom correspondence should be addressed. E-mail: iat1{at}columbia.edu.


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Abstract

Two features of advanced atherosclerotic lesions are large numbers of macrophages and a heightened state of inflammation. Some of the macrophages appear to be enriched with free cholesterol (FCM{phi}s), and we have shown that this process induces the synthesis and secretion of inflammatory cytokines, including TNF-{alpha} and IL-6. However, lesions contain many other macrophages that are not FC-enriched (non-FCM{phi}s). Therefore, we sought to understand how the interaction of these two populations of macrophages would influence the inflammatory response. We show here that non-FCM{phi}s possess a robust ability to deplete TNF-{alpha} and IL-6 secreted by FCM{phi}s. The mechanism involves enhanced pinocytic uptake and lysosomal degradation of the FCM{phi}-secreted cytokines by the non-FCM{phi}s. It is remarkable that the FCM{phi}s contribute directly to this process by secreting pinocytosis-stimulatory factors, which act on non-FCM{phi}s but not on the FCM{phi}s themselves. One of these pinocytosis-stimulatory factors is M-CSF, which is induced by a process involving cholesterol trafficking to the endoplasmic reticulum and signaling through PI-3K and ERK MAPK pathways. However, one or more other FCM{phi}-secreted factors are also required for stimulating pinocytosis in non-FCM{phi}s. Thus, FCM{phi}s secrete inflammatory cytokines as well as factors that promote the eventual pinocytosis and degradation of these cytokines by neighboring macrophages. This process may normally serve to prevent prolonged or disseminated effects of inflammatory cytokines during inflammation, and possible perturbation of stimulated pinocytosis during the progression of advanced atherosclerosis may contribute to the heightened inflammatory state of these lesions.

Key Words: TNF • M-CSF • atherosclerosis




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