Objectives Apolipoprotein E (apoE) exerts potent anti-inflammatory effects. We here investigated the effect of apoE on the functional phenotype of macrophages. Methods and Results Human apoE receptors VLDL-R or apoER2 were stably expressed in RAW264.7 mouse macrophages. In these cells apoE downregulated markers of the pro-inflammatory M1 phenotype (iNOS, IL-12, MIP-1α), but upregulated markers of the anti-inflammatory M2 phenotype (arginase-I, SOCS3, IL-1RA). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis) as well as poly(I:C)- and/or IFN-γ-induced production of pro-inflammatory cytokines, COX-2 expression, and activation of NF-κB, IκB and STAT1 were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice, but not wild type or LDL receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38MAP kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38MAP kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE−/− mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression). Conclusion ApoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This effect may represent a novel anti-inflammatory activity of apoE.
The gram-positive soil bacterium Arthrobacter nicotinovorans (formerly known as Arthrobacter oxidans and reclassified by Kodama et al. [22]) has the ability to use nicotine as its sole carbon and energy source (8,10,15,17). Nicotine, the alkaloid of the tobacco plant, is synthesized as the L-isomer, and the first enzyme to attack L-nicotine is a trimeric, molybdopterin cofactor (MoCo) (most probably in its dinucleotide form [18])-, flavin adenine dinucleotide (FAD)-, and [Fe-S] clustercontaining nicotine dehydrogenase (NDH), which hydroxylates the pyridine ring at position 6 (Fig.
Objectives-Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1 (IL-1), a proinflammatory cytokine present in atherosclerotic lesions. Methods and Results-IL-1-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-B and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1 signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1 signaling intermediates revealed that NF-B transactivation was inhibited by apoE in MyD88-and IRAK1-but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1 signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1 signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-␣ or polyinosinic:polycytidylic acid. A polipoprotein E (apoE) is a major protein component of plasma lipoproteins and plays an important role in preventing atherosclerosis. The antiatherogenic effects of apoE are usually attributed to its ability to promote cholesterol efflux from peripheral cells for reverse cholesterol transport and to facilitate hepatic clearance of very low density lipoprotein (VLDL) and chylomicron remnants. However, apoE protects against atherosclerosis even in experimental settings, in which its effects on plasma cholesterol are negligible. For instance, transgenic expression of apoE in arterial wall led to inhibition of atheroma formation without affecting plasma lipoprotein profile. 1,2 Conversely, acceleration of atherosclerosis was observed in apoE ϩ/ϩ animals after transplantation of bone marrow from apoE-deficient mouse. 3 These results suggest that apoE directly inhibits the development of atherosclerosis in a manner independent of its role in cholesterol transport. Conclusion-ApoEAtherosclerosis is commonly regarded as a chronic inflammatory disease. Inflammation mediators such as cytokines and chemokines were shown to significantly contribute to the formation of atherosclerotic lesions, whereas antiinflammatory factors play the opposite role. ApoE has been previously suggested to suppress the expression of adhesion molecules on endothelial surface and thereby to prevent monocyte recruitment into the arterial intima. 4 However, little information is available concerning the involvement of apoE in initiation and perpetuation of inflammation within the vascular wall. In the present study, we examined the influence of apoE on cellular effects of interleukin-1 (IL-1), a proinflammatory cytok...
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