Oxidized LDLs Inhibit TLR-induced IL-10 Production by Monocytes: A New Aspect of Pathogen-Accelerated Atherosclerosis
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Oxidized LDLs Inhibit TLR-induced IL-10 Production by Monocytes: A New Aspect of Pathogen-Accelerated Atherosclerosis Małgorzata Bzowska,1 Anna Nogieć,1 Joanna Skrzeczyńska-Moncznik,1 Barbara Mickowska,2 Krzysztof Guzik,1,3 and Juliusz Pryjma1
Abstract—It is widely accepted that oxidized low-density lipoproteins and local infections or endotoxins in circulation contribute to chronic inflammatory process at all stages of atherosclerosis. The hallmark cells of atherosclerotic lesions—monocytes and macrophages—are able to detect and integrate complex signals derived from lipoproteins and pathogens, and respond with a spectrum of immunoregulatory cytokines. In this study, we show strong inhibitory effect of oxLDLs on antiinflammatory interleukin-10 production by monocytes responding to TLR2 and TLR4 ligands. In contrast, pro-inflammatory tumor necrosis factor secretion was even slightly increased, when stimulated with lipopolysaccharide from Porphyromonas gingivalis—an oral pathogen associated with atherosclerosis. The oxLDLs modulatory activity may be explained by altered recognition of pathogen-associated molecular patterns, which involves serum proteins, particularly vitronectin. We also suggest an interaction between vitronectin receptor, CD11b, and TLR2. The presented data support a novel pathway for pathogen-accelerated atherosclerosis, which relies on oxidized lowdensity lipoprotein-mediated modulation of anti-inflammatory response to TLR ligands. KEY WORDS: IL-10; TLR; monocytes; lipoproteins; atherosclerosis.
INTRODUCTION Atherosclerotic vascular disease remains the most common cause of death and disability in westernized countries. Although atherosclerosis was recognized for many years as a simple lipid storage disease, nowadays, it is widely accepted that both—disturbed lipid metabolism leading to accumulation of low-density lipoproElectronic supplementary material The online version of this article (doi:10.1007/s10753-012-9472-3) contains supplementary material, which is available to authorized users. 1
Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland 2 Malopolska Centre of Food Monitoring and Certification, Faculty of Food Technology, Agricultural University, Balicka 122, 30-149 Kraków, Poland 3 To whom correspondence should be addressed at Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. E-mail: [email protected]
teins (LDLs) in the arteries and chronic inflammation of the vascular wall—are the most prominent features of this illness [1, 2]. Even though, oxidized forms of lowdensity lipoproteins (oxLDLs) are major risk factor, recently accumulating evidences have implicated that infectious agents can accelerate atherosclerosis [3–5]. It has been documented that certain chronic infections such as periodontitis and chlamydial infection exacerbate clinical manifestation of atherosclerosis [6, 7]. The presence of th
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