Location: Arkansas Children Nutrition Center
Title: OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD35 Authors
|Xie, Chenghui -|
|Ng, Hongkui -|
|Nagarajan, Shanumgam -|
Submitted to: Immunology Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 21, 2011
Publication Date: February 15, 2011
Citation: Xie, C., Ng, H., Nagarajan, S. 2011. OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD35. Immunology Letters. 137(1):15-27. Interpretive Summary: Uptake of lipids, bad cholesterol, or LDL, onto the blood vessels is one of the risk factors for the development of atherosclerosis. In our body, these lipids undergo chemical modifications resulting in a modified-form of these lipids. These modified-lipids are recognized by a group of receptors called scavenger receptors. We have shown soy, rice and blueberry diet prevents the progression of atherosclerosis. We aimed to identify bioactive compound(s) present in the diet. To identify these factors we have developed a novel bioassay using macrophages. Finding from this study showed oxLDL binding to macrophages could induce activation of these cells. This activation results in enhanced expression of pro-inflammatory cytokines. We will use this bioassay to identify and characterize bioactive components of dietary factors present in soy, blueberry, and other diets.
Technical Abstract: OxLDL binding to CD36 is shown to result in macrophage activation and foam cell formation that have been implicated in atherosclerosis. However, CD36 has also been shown to induce inflammatory response to other ligands besides oxLDL. During the course of blocking CD36 oxLDL binding function using anti CD36 antibodies, we have identified a novel domain of CD36 that triggers inflammatory response-independent of oxLDL binding. OxLDL bound to the mouse reporter cell line RAW-Blue induced TNF-a and RANTES mRNA and protein expression. Pretreatment of RAW-Blue cells with an anti-mCD36 mAb, JC63.1, an activating mCD36 mAb, surprisingly did not inhibit oxLDL-induced response. Further, binding of this antibody to CD36 alone induced a pro-inflammatory cytokine response in RAW-Blue cells as well as primary mouse macrophages. The induction of cytokine response was specific only to this antibody and was CD36-dependent, since CD36 macrophages failed to induce a similar response. The interaction of the antibody to CD36 led to activation of NF-'B and MAP kinase. Notably, a CD36 peptide blocked oxLDL-induced foam cell formation and macrophage activation. However, the activating mCD36 mAb induced macrophage activation was not inhibited by CD36 peptide. Further, activating mCD36 mAb enhanced oxLDL- or TLR2- or TLR4-mediated inflammatory responses. Collectively, our data provide evidence that activating mCD36 mAb binds to a domain different from the oxLDL-binding domain on mouse CD36, and suggest that interaction at this domain may contribute to oxLDL-independent macrophage inflammatory responses that lead to chronic inflammatory diseases.