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Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages

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Lipids

Abstract

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.

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Abbreviations

Anti-phospho-JNK:

anti-phospho-Jun Amino-terminal activated kinase

BIM:

bisindolylmaleimide 1

ECL:

enhanced chemiluminescence

ERK:

extracellular signal-regulated kinase

G3PDH:

glyceraldehyde-3-phosphate dehydrogenase

GM-CSF:

granulocyte macrophage-colony stimulating factor

HRP:

horseradish peroxidase

JNK:

Jun amino-terminal activated kinase

MAP:

kinase, mitogen-activated protein kinase

M-CSF:

macrophage-colony stimulating factor

MEK:

MAP kinase/ERK kinase

MEK 1/2:

MAP kinase kinase

NEFA:

nonesterified fatty acids

nifedipine:

1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester

PD 098059:

2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

PKC:

protein kinase C

PMA:

phorbol myristate acetate

RT:

reverse transcriptase

SAPK:

stress-activated protein kinase

TBS-T:

5% nonfat dried milk in 20 mM Tris, pH 7.6, 138 mM NaCl, and 0.1% Tween-20

References

  1. von Eckardstein, A., and Assman, G. (2000) Prevention of Coronary Heart Disease by Raising High-Density Lipoprotein Cholesterol, Curr. Opin. Lipidol. 11, 627–637.

    Article  Google Scholar 

  2. Lehto, S., Rönnema, T., Haffner, S., Pyörälä, K., Kallio, V., and Laakso, M. (1997) Dyslipidemia and Hyperglycemia Predict Coronary Heart Disease Events in Middle-Aged Patients with NIDDM, Diabetes 46, 1354–1359.

    PubMed  CAS  Google Scholar 

  3. Reaven, G.M., Hollenbeck, C., Jeng, C.Y., Wu, M.S., and Chen, Y.D. (1988) Measurement of Plasma Glucose, Free Fatty Acid, Lactate, and Insulin for 24 h in Patients with NIDDM, Diabetes 37, 1020–1024.

    PubMed  CAS  Google Scholar 

  4. Camejo, G., Olsson, U., Hurt-Camejo, E., Bahramian, N., and Bondjers, G. (2002) The Extracellular Matrix on Atherogenesis and Diabetes-Associated Vascular Disease, Atheroscler. Suppl. 3, 3–9.

    Article  PubMed  CAS  Google Scholar 

  5. Willson, T.M., Brown, P.J., Sternbach, D.D., and Henke, B.R. (2000) The PPARs: From Orphan Receptors to Drug Discovery, J. Med. Chem. 43, 527–550.

    Article  PubMed  CAS  Google Scholar 

  6. Hennig, B., Lipke, D.W., Biossonneault, G.A., and Ramasamy, S. (1995) Role of Fatty Acids and Eicosanoids in Modulating Proteoglycan Metabolism in Endothelial Cells, Prostaglandins Leukot. Essent. Fatty Acids 53, 315–324.

    Article  PubMed  CAS  Google Scholar 

  7. Hennig, B., Meerarani, P., Ramadass, P., Watkins, B.A., and Toborek, M. (2000) Fatty Acid-Mediated Activation of Vascular Endothelial Cells, Metabolism 49, 1006–1013.

    Article  PubMed  CAS  Google Scholar 

  8. Olsson, U., Bondjers, G., and Camejo, G. (1999) Fatty Acids Modulate the Composition of Extracellular Matrix in Cultured Human Arterial Smooth Muscle Cells by Altering the Expression of Genes for Proteoglycan Core Proteins, Diabetes 48, 616–622.

    PubMed  CAS  Google Scholar 

  9. Steinberg, D., and Witztum, J. (1999) Lipoproteins, Lipoprotein Oxidation and Atherogenesis, in Molecular Basis of Cardiovascular Disease (Breslow, J., Leiden, J., Rosenberg, R., and Seidman, C., eds.), pp. 458–475, W. B. Saunders, Philadelphia.

    Google Scholar 

  10. Langstein, J., Michel, J., and Schwarz, H. (1999) CD137 Induces Proliferation and Endomitosis in Monocytes, Blood 94, 3161–3168.

    PubMed  CAS  Google Scholar 

  11. Ross, R. (1999) Atherosclerosis—An Inflammatory Disease, N. Engl. J. Med. 340, 115–126.

    Article  PubMed  CAS  Google Scholar 

  12. Biwa, T., Sakai, M., Matsumura, T., Kobori, S., Kaneko, K., Miyazaki, A., Hakamata, H., Horiuchi, S., and Shichiri, M. (2000) Sites of Action of Protein Kinase C and Phosphatidylinositol 3-Kinase Are Distinct in Oxidized Low Density Lipoprotein-Induced Macrophage Proliferation, J. Biol. Chem. 275, 5810–5816.

    Article  PubMed  CAS  Google Scholar 

  13. Esterbauer, H. (1995) The Chemistry of Oxidation of Lipoproteins, in Oxidative Stress, Lipoproteins and Cardiovascular Dysfunction (Rice-Evans, C., and Bruckdorfer, K., eds.), pp. 55–79, Portland Press, London.

    Google Scholar 

  14. Montell, E., Turini, M., Marotta, M., Roberts, M., Noe, V., Ciudad, C.J., Mace, K., and Gomez-Foix, A.M. (2001) DAD Accumulation from Saturated Fatty Acids Desensitizes Insulin Stimulation of Glucose Uptake in Muscle Cells, Am. J. Physiol. Endocrinol. Metab. 280, E229-E237.

    PubMed  CAS  Google Scholar 

  15. Lie, Y.S., and Petropoulos, C.J. (1998) Advances in Quantitative PCR Technology: 5′ Nuclease Assays, Curr. Opin. Biotechnol. 9, 43–48.

    Article  PubMed  CAS  Google Scholar 

  16. Bradford, M.M. (1976) A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding, Anal. Biochem. 72, 248–254.

    Article  PubMed  CAS  Google Scholar 

  17. Hurt-Camejo, E., Camejo, G., Rosengren, B., Lopez, F., Wiklund, O., and Bonjders, G. (1990) Differential Uptake of Proteoglycan-Selected Subfractions of Low Density Lipoprotein by Human Macrophages, J. Lipid Res. 31, 1387–1398.

    PubMed  CAS  Google Scholar 

  18. Homan, R., and Anderson, M.K. (1998) Rapid Separation and Quantitation of Combined Neutral and Polar Lipid Classes by High-Performance Liquid Chromatography and Evaporative Light-Scattering Mass Detection, J. Chromatogr. B Biomed. Sci. Appl. 708, 21–26.

    Article  PubMed  CAS  Google Scholar 

  19. Newton, A.C. (1995) Protein Kinase C: Structure, Function, and Regulation, J. Biol. Chem. 270, 28495–28498.

    Article  PubMed  CAS  Google Scholar 

  20. Garrington, T., and Johnson, G. (1999) Organization and Regulation of Mitogen-Activated Protein Kinase Signaling Pathways, Cur. Opin. Cell Biol. 11, 211–218.

    Article  CAS  Google Scholar 

  21. Rao, M.K. (2001) MAP Kinase Activation in Macrophages, J. Leukoc. Biol. 69, 3–10.

    PubMed  CAS  Google Scholar 

  22. Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T., and Saltei, A.R. (1995) PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-Activated Protein Kinase Kinase in vitro and in vivo, J. Biol. Chem. 270, 27489–27494.

    Article  PubMed  CAS  Google Scholar 

  23. Bergman, R.N., and Ader, M. (2000) Free Fatty Acids and Pathogenesis of Type 2 Diabetes Mellitus, Trends Endocrinol. Metab. 11, 351–356.

    Article  PubMed  CAS  Google Scholar 

  24. Carlsson, M., Wessman, Y., Almgren, P., and Groop, L. (2000) High Levels of Nonesterified Fatty Acids Are Associated with Increased Familial Risk of Cardiovascular Disease, Arterioscler. Thromb. Vasc. Biol. 20, 1588–1594.

    PubMed  CAS  Google Scholar 

  25. Mingrone, G., DeGaetano, A., Greco, A.V., Capristo, E., Benedetti, G., Castagneto, M., and Gasbarrini, G. (1997) Reversibility of Insulin Resistance in Obese Diabetic Patients: Role of Plasma Lipids, Diabetologia 40, 599–605.

    Article  PubMed  CAS  Google Scholar 

  26. Sakai, M., Kobori, S., Miyazaki, A., and Horiuchi, S. (2000) Macrophage Proliferation in Atherosclerosis, Curr. Opin. Lipidol. 11, 503–509.

    Article  PubMed  CAS  Google Scholar 

  27. Plenz, G., Reichenberg, S., Koenig, C., Rauterberg, J., Deng, M.C., Baba, H.A., and Robenek, H. (1999) Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Modulates the Expression of Type VIII Collagen mRNA in Vascular Smooth Muscle Cells and Both Are Codistributed During Atherogenesis, Arterioscler. Thromb. Vasc. Biol. 19, 1658–1668.

    PubMed  CAS  Google Scholar 

  28. Sugiyama, S., Okada, Y., Sukhova, G.K., Virmani, R., Heinecke, J.W., and Libby, P. (2001) Macrophage Myeloperoxidase Regulation by Granulocyte Macrophage Colony-Stimulating Factor in Human Atherosclerosis and Implications in Acute Coronary Syndromes, Am. J. Pathol. 158, 879–891.

    PubMed  CAS  Google Scholar 

  29. Griffin, M.E., Marcucci, M.J., Cline, G.W., Bell, K., Barucci, N., Lee, D., Goodyear, L.J., Kraegen, E.W., White, M.F., and Shulman, G.I. (1999) Free Fatty Acid-Induced Insulin Resistance Is Associated with Activation of Protein Kinase C Φ and Alterations in the Insulin Signaling Cascade, Diabetes 48, 1270–1274.

    PubMed  CAS  Google Scholar 

  30. Kraegen, E.W., Cooney, G.J., Ye, J., and Thompson, A.L. (2001) Triglycerides, Fatty Acids and Insulin Resistance—Hyperinsulinemia, Experim. Clin. Endocrin. Diabetes 109, S516-S526.

    Article  CAS  Google Scholar 

  31. McGarry, J.D. (2002) Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes, Diabetes, 51, 7–18.

    PubMed  CAS  Google Scholar 

  32. Liu, W.S., and Heckman, C.A. (1998) The Sevenfold Way of PKC Regulation, Cell Signal. 10, 529–542.

    Article  PubMed  CAS  Google Scholar 

  33. Nishizuka, Y. (1995) Protein Kinase C and Lipid Signaling for Sustained Cellular Responses, FASEB J. 9, 484–496.

    PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

    Nahid Bahramian, Gunnel Östergren-Lundén, Göran Bondjers & Urban Olsson

Authors
  1. Nahid Bahramian
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  2. Gunnel Östergren-Lundén
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  3. Göran Bondjers
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  4. Urban Olsson
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Corresponding author

Correspondence to Urban Olsson.

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Bahramian, N., Östergren-Lundén, G., Bondjers, G. et al. Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages. Lipids 39, 243–249 (2004). https://doi.org/10.1007/s11745-004-1226-2

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  • DOI: https://doi.org/10.1007/s11745-004-1226-2

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