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Influence of oxidatively modified LDL on monocyte-macrophage differentiation

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Abstract

Transendothelial migration of peripheral blood mononuclear cells (PBMCs) and their subsequent interaction with the subendothelial matrix lead to their differentiation to macrophages (mϕs). To study whether preexposure of monocytes in circulation to modified proteins influences their differentiation to mϕs, an in vitro model system using isolated PBMC in culture was used. The effect of modified proteins such as oxidatively modified LDL (ox-LDL), acetylated and non-enzymatically glycated-BSA (NEG-BSA) on the differentiation process was studied by monitoring the upregulation of mϕ specific functions such as endocytosis, production of matrix metalloproteinases (MMPs), expression of surface antigen, activity of β-glucuronidase and down regulation of monocyte specific myeloperoxidase activity. Rate of endocytosis, production of MMPs and β-glucuronidase activity were significantly greater in cells treated with modified proteins irrespective of the nature of modification. Both CuSO4 ox-LDL and HOCl ox-LDL increased the rate of expression of the mϕ specific functions. FACS analysis showed that the rate of upregulation of mϕ specific CD71 and down regulation of monocyte specific CD14 were high in cells supplemented with modified proteins. Studies using PPARγ antagonist and agonist suggest its involvement in CuSO4 ox-LDL induced monocyte-macrophage (mo-mϕ) differentiation whereas the expression of macrophage specific functions in cells exposed to other modified proteins was independent of PPARγ. PBMC isolated from hypercholesterolemic rabbits in culture expressed mϕ specific functions at a faster rate compared to normal controls indicating that these observations are relevant in vivo. These results indicate that preexposure of monocytes to modified proteins promote their differentiation to mϕs and may serve as a feed forward type control for clearing modified proteins.

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Acknowledgements

Financial assistance received from the Indian Council of Medical Research to A. Radhika in the form of SRF is gratefully acknowledged. We thank Dr. Padma Shastry, Scientist F, National Centre for Cell Science, Pune, India, for providing the necessary guidance and facilities in doing FACS.

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  1. Shiney S. Jacob

    Present address: Kings College, University of London, London, UK

Authors and Affiliations

  1. Department of Biochemistry, University of Kerala, Kariavattom, Trivandrum, 695 581, India

    Achuthan Radhika, Shiney S. Jacob & Perumana R. Sudhakaran

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  1. Achuthan Radhika
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Correspondence to Perumana R. Sudhakaran.

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Radhika, A., Jacob, S.S. & Sudhakaran, P.R. Influence of oxidatively modified LDL on monocyte-macrophage differentiation. Mol Cell Biochem 305, 133–143 (2007). https://doi.org/10.1007/s11010-007-9536-0

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