Abstract
BackgroundOxidized low-density lipoprotein (oxLDL) mediates the transformation of macrophages (MΦ) to cholesterol-rich foam cells and the release of pro-inflammatory cytokines during atherogenesis. JAB1 (Jun activation domain binding protein-1) is present in all stages of human plaques, involved in the Toll-like receptor-mediated activation of p38 mitogen-activated protein kinase (MAPK) and controls nuclear factor-kappa B (NF-κB) activation. Thus, we were interested in the role of JAB1 during foam cell formation of MΦ after oxLDL exposition.Methods and resultsWe found that JAB1 was present in CD68-immunoreactive (−ir) MΦ in atherosclerotic plaques of apolipoprotein E knockout (ApoE−/−) mice after a high cholesterol/fat diet. Furthermore, differentiated human U937 MΦ - incubated with oxLDL (4 h) to induce foam cell formation – showed a significant increase of JAB1 (50 μg/ml: 1.39 + 0.15-fold; 100 μg/ml: 1.80 + 0.26-fold; 200 μg/ml: 2.05 + 0.30-fold; p < 0.05) on the protein level compared to the control. Independent from JAB1 silencing, we found an increase of total cholesterol (TC), free cholesterol (FC) and cholesteryl ester (CE) after oxLDL exposition. However, siJAB1-MФ showed a reduction of tumor necrosis factor-alpha (TNF-α) (36%; p < 0.05 vs. non-transfected MФ) and interleukin (IL)-6 (30%; p < 0.05 vs. non-transfected MФ) mRNA expression, as well as TNF-α (46%; p < 0.05 vs. non-transfected MФ) and IL-6 (32%; p < 0.05 vs. non-transfected MФ) protein secretion after oxLDL exposition. In parallel with an upregulation of inflammatory cytokines (TNF-α, IL-6) after oxLDL exposition, we found a significant (p < 0.05) increase of 37% in p38 MAPK activation after 4 h oxLDL-treatment, independent from NF-kB signaling. In this context, we showed regional co-localization of JAB1 with p38 MAPK in atherosclerotic plaques of ApoE−/− mice. Moreover, we detected interaction of JAB1 with p38 MAPK in U937 cells.ConclusionWe demonstrate that oxLDL induces JAB1 expression and influences its cellular localization, whereby the p38 MAPK signaling pathway is modified with consequences for inflammation of human MΦ in foam cells and atherosclerotic lesions.
Highlights
Oxidized low-density lipoprotein mediates the transformation of macrophages (MΦ) to cholesterol-rich foam cells and the release of pro-inflammatory cytokines during atherogenesis
We demonstrate that Oxidized low-density lipoprotein (oxLDL) induces Jun activation domain binding protein-1 (JAB1) expression and influences its cellular localization, whereby the p38 mitogen-activated protein kinase (MAPK) signaling pathway is modified with consequences for inflammation of human MΦ in foam cells and atherosclerotic lesions
Since our immunohistochemical stainings of the brachiocephalic trunk of ApoE−/− mice revealed a co-localization of JAB1-ir and CD68-ir MФ (Fig. 1e, f ), we investigated the effect of oxLDL in PMAdifferentiated human U937 MΦ on JAB1 protein expression and foam cell formation in vitro
Summary
Oxidized low-density lipoprotein (oxLDL) mediates the transformation of macrophages (MΦ) to cholesterol-rich foam cells and the release of pro-inflammatory cytokines during atherogenesis. JAB1 (Jun activation domain binding protein-1) is present in all stages of human plaques, involved in the Toll-like receptor-mediated activation of p38 mitogen-activated protein kinase (MAPK) and controls nuclear factor-kappa B (NF-κB) activation. MΦ which internalized oxLDL via scavenger receptors subsequently transform into lipidladen foam cells [3] and release various pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) under the transcription control of NF-κB - upon exposure to oxLDL [4]. Ik-Bα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) binds to NF-κB, a complex which remains in the cytosol when inactive. NF-κB activation controls the Ik-Bα expression with an auto-regulatory negative feedback loop [6]
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