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. 2001 Feb 15;354(Pt 1):179–187. doi: 10.1042/0264-6021:3540179

Comparison of macrophage responses to oxidized low-density lipoprotein and macrophage colony-stimulating factor (M-CSF or CSF-1).

J A Hamilton 1, R Byrne 1, W Jessup 1, V Kanagasundaram 1, G Whitty 1
PMCID: PMC1221642  PMID: 11171093

Abstract

Modification of low-density lipoprotein (LDL), for example by oxidation, could be involved in foam cell formation and proliferation observed in atherosclerotic lesions. Macrophage colony-stimulating factor (CSF-1 or M-CSF) has been implicated in foam cell development. It has been reported previously that oxidized LDL (ox.LDL) and CSF-1 synergistically stimulate DNA synthesis in murine bone-marrow-derived macrophages (BMM). The critical signal-transduction cascades responsible for the proliferative response to ox.LDL, as well as their relationship to those mediating CSF-1 action, are unknown. We report here that ox.LDL stimulated extracellular signal-regulated protein kinase (ERK)-1, ERK-2 and phosphoinositide 3-kinase activities in BMM but to a weaker extent than optimal CSF-1 concentrations at the time points examined. Inhibitor studies suggested at least a partial role for these kinases, as well as p70 S6-kinase, in ox.LDL-induced macrophage survival and DNA synthesis. For the DNA synthesis response to CSF-1, the degree of inhibition by PD98059, wortmannin and rapamycin was significant at low CSF-1 concentrations but was reduced as the CSF-1 dose increased. Using BMM from CSF-1-deficient mice (op/op) and a neutralizing antibody approach, we found no evidence for an essential role for endogenous CSF-1 in ox.LDL-mediated survival or DNA synthesis; likewise, with the same approaches, no evidence was obtained for an essential role for endogenous granulocyte/macrophage-CSF in ox.LDL-mediated macrophage survival and, in contrast with the literature, ox.LDL-induced macrophage DNA synthesis.

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Selected References

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  1. Bartocci A., Pollard J. W., Stanley E. R. Regulation of colony-stimulating factor 1 during pregnancy. J Exp Med. 1986 Sep 1;164(3):956–961. doi: 10.1084/jem.164.3.956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Becker S., Warren M. K., Haskill S. Colony-stimulating factor-induced monocyte survival and differentiation into macrophages in serum-free cultures. J Immunol. 1987 Dec 1;139(11):3703–3709. [PubMed] [Google Scholar]
  3. Biwa T., Hakamata H., Sakai M., Miyazaki A., Suzuki H., Kodama T., Shichiri M., Horiuchi S. Induction of murine macrophage growth by oxidized low density lipoprotein is mediated by granulocyte macrophage colony-stimulating factor. J Biol Chem. 1998 Oct 23;273(43):28305–28313. doi: 10.1074/jbc.273.43.28305. [DOI] [PubMed] [Google Scholar]
  4. Biwa T., Sakai M., Matsumura T., Kobori S., Kaneko K., Miyazaki A., Hakamata H., Horiuchi S., Shichiri M. Sites of action of protein kinase C and phosphatidylinositol 3-kinase are distinct in oxidized low density lipoprotein-induced macrophage proliferation. J Biol Chem. 2000 Feb 25;275(8):5810–5816. doi: 10.1074/jbc.275.8.5810. [DOI] [PubMed] [Google Scholar]
  5. Brown A. J., Dean R. T., Jessup W. Free and esterified oxysterol: formation during copper-oxidation of low density lipoprotein and uptake by macrophages. J Lipid Res. 1996 Feb;37(2):320–335. [PubMed] [Google Scholar]
  6. Brown A. J., Mander E. L., Gelissen I. C., Kritharides L., Dean R. T., Jessup W. Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells. Accumulation of oxidized esters in lysosomes. J Lipid Res. 2000 Feb;41(2):226–237. [PubMed] [Google Scholar]
  7. Campbell I. K., Rich M. J., Bischof R. J., Dunn A. R., Grail D., Hamilton J. A. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol. 1998 Oct 1;161(7):3639–3644. [PubMed] [Google Scholar]
  8. Cecchini M. G., Dominguez M. G., Mocci S., Wetterwald A., Felix R., Fleisch H., Chisholm O., Hofstetter W., Pollard J. W., Stanley E. R. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994 Jun;120(6):1357–1372. doi: 10.1242/dev.120.6.1357. [DOI] [PubMed] [Google Scholar]
  9. Filonzi E. L., Zoellner H., Stanton H., Hamilton J. A. Cytokine regulation of granulocyte-macrophage colony stimulating factor and macrophage colony-stimulating factor production in human arterial smooth muscle cells. Atherosclerosis. 1993 Mar;99(2):241–252. doi: 10.1016/0021-9150(93)90026-q. [DOI] [PubMed] [Google Scholar]
  10. Gordon D., Reidy M. A., Benditt E. P., Schwartz S. M. Cell proliferation in human coronary arteries. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4600–4604. doi: 10.1073/pnas.87.12.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamilton J. A., Byrne R., Whitty G., Vadiveloo P. K., Marmy N., Pearson R. B., Christy E., Jaworowski A. Effects of wortmannin and rapamycin on CSF-1-mediated responses in macrophages. Int J Biochem Cell Biol. 1998 Feb;30(2):271–283. doi: 10.1016/s1357-2725(97)00111-8. [DOI] [PubMed] [Google Scholar]
  12. Hamilton J. A., Chan J., Byrne R. J., Bischof R. J., Jaworowski A., Kanagasundaram V. MRL/lpr and MRL+/+ macrophage DNA synthesis in the absence and the presence of colony-stimulating factor-1 and granulocyte-macrophage colony-stimulating factor. J Immunol. 1998 Dec 15;161(12):6802–6811. [PubMed] [Google Scholar]
  13. Hamilton J. A., Myers D., Jessup W., Cochrane F., Byrne R., Whitty G., Moss S. Oxidized LDL can induce macrophage survival, DNA synthesis, and enhanced proliferative response to CSF-1 and GM-CSF. Arterioscler Thromb Vasc Biol. 1999 Jan;19(1):98–105. doi: 10.1161/01.atv.19.1.98. [DOI] [PubMed] [Google Scholar]
  14. Hamilton J. A., Vairo G., Lingelbach S. R. Activation and proliferation signals in murine macrophages: stimulation of glucose uptake by hemopoietic growth factors and other agents. J Cell Physiol. 1988 Mar;134(3):405–412. doi: 10.1002/jcp.1041340311. [DOI] [PubMed] [Google Scholar]
  15. Hamilton J., Vassalli J. D., Reich E. Macrophage plasminogen activator: induction by asbestos is blocked by anti-inflammatory steroids. J Exp Med. 1976 Dec 1;144(6):1689–1694. doi: 10.1084/jem.144.6.1689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jaworowski A., Christy E., Yusoff P., Byrne R., Hamilton J. A. Differences in the kinetics of activation of protein kinases and extracellular signal-related protein kinase 1 in colony-stimulating factor 1-stimulated and lipopolysaccharide-stimulated macrophages. Biochem J. 1996 Dec 15;320(Pt 3):1011–1016. doi: 10.1042/bj3201011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jaworowski A., Wilson N. J., Christy E., Byrne R., Hamilton J. A. Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal. J Biol Chem. 1999 May 21;274(21):15127–15133. doi: 10.1074/jbc.274.21.15127. [DOI] [PubMed] [Google Scholar]
  18. Kanagasundaram V., Jaworowski A., Hamilton J. A. Association between phosphatidylinositol-3 kinase, Cbl and other tyrosine phosphorylated proteins in colony-stimulating factor-1-stimulated macrophages. Biochem J. 1996 Nov 15;320(Pt 1):69–77. doi: 10.1042/bj3200069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Katsuda S., Coltrera M. D., Ross R., Gown A. M. Human atherosclerosis. IV. Immunocytochemical analysis of cell activation and proliferation in lesions of young adults. Am J Pathol. 1993 Jun;142(6):1787–1793. [PMC free article] [PubMed] [Google Scholar]
  20. Kelley T. W., Graham M. M., Doseff A. I., Pomerantz R. W., Lau S. M., Ostrowski M. C., Franke T. F., Marsh C. B. Macrophage colony-stimulating factor promotes cell survival through Akt/protein kinase B. J Biol Chem. 1999 Sep 10;274(37):26393–26398. doi: 10.1074/jbc.274.37.26393. [DOI] [PubMed] [Google Scholar]
  21. L'Allemain G. Deciphering the MAP kinase pathway. Prog Growth Factor Res. 1994;5(3):291–334. doi: 10.1016/0955-2235(94)90011-6. [DOI] [PubMed] [Google Scholar]
  22. Martens J. S., Lougheed M., Gómez-Muñoz A., Steinbrecher U. P. A modification of apolipoprotein B accounts for most of the induction of macrophage growth by oxidized low density lipoprotein. J Biol Chem. 1999 Apr 16;274(16):10903–10910. doi: 10.1074/jbc.274.16.10903. [DOI] [PubMed] [Google Scholar]
  23. Martens J. S., Reiner N. E., Herrera-Velit P., Steinbrecher U. P. Phosphatidylinositol 3-kinase is involved in the induction of macrophage growth by oxidized low density lipoprotein. J Biol Chem. 1998 Feb 27;273(9):4915–4920. doi: 10.1074/jbc.273.9.4915. [DOI] [PubMed] [Google Scholar]
  24. Matsumura T., Sakai M., Matsuda K., Furukawa N., Kaneko K., Shichiri M. Cis-acting DNA elements of mouse granulocyte/macrophage colony-stimulating factor gene responsive to oxidized low density lipoprotein. J Biol Chem. 1999 Dec 31;274(53):37665–37672. doi: 10.1074/jbc.274.53.37665. [DOI] [PubMed] [Google Scholar]
  25. Rajavashisth T. B., Andalibi A., Territo M. C., Berliner J. A., Navab M., Fogelman A. M., Lusis A. J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990 Mar 15;344(6263):254–257. doi: 10.1038/344254a0. [DOI] [PubMed] [Google Scholar]
  26. Rajavashisth T. B., Yamada H., Mishra N. K. Transcriptional activation of the macrophage-colony stimulating factor gene by minimally modified LDL. Involvement of nuclear factor-kappa B. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1591–1598. doi: 10.1161/01.atv.15.10.1591. [DOI] [PubMed] [Google Scholar]
  27. Rekhter M. D., Gordon D. Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques. Am J Pathol. 1995 Sep;147(3):668–677. [PMC free article] [PubMed] [Google Scholar]
  28. Rosenfeld M. E., Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990 Sep-Oct;10(5):680–687. doi: 10.1161/01.atv.10.5.680. [DOI] [PubMed] [Google Scholar]
  29. Rosenfeld M. E., Ylä-Herttuala S., Lipton B. A., Ord V. A., Witztum J. L., Steinberg D. Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol. 1992 Feb;140(2):291–300. [PMC free article] [PubMed] [Google Scholar]
  30. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  31. Sakai M., Biwa T., Matsumura T., Takemura T., Matsuda H., Anami Y., Sasahara T., Kobori S., Shichiri M. Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. Arterioscler Thromb Vasc Biol. 1999 Jul;19(7):1726–1733. doi: 10.1161/01.atv.19.7.1726. [DOI] [PubMed] [Google Scholar]
  32. Sakai M., Miyazaki A., Hakamata H., Sasaki T., Yui S., Yamazaki M., Shichiri M., Horiuchi S. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem. 1994 Dec 16;269(50):31430–31435. [PubMed] [Google Scholar]
  33. Sakai M., Miyazaki A., Hakamata H., Sato Y., Matsumura T., Kobori S., Shichiri M., Horiuchi S. Lysophosphatidylcholine potentiates the mitogenic activity of modified LDL for human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol. 1996 Apr;16(4):600–605. doi: 10.1161/01.atv.16.4.600. [DOI] [PubMed] [Google Scholar]
  34. Salomon R. N., Underwood R., Doyle M. V., Wang A., Libby P. Increased apolipoprotein E and c-fms gene expression without elevated interleukin 1 or 6 mRNA levels indicates selective activation of macrophage functions in advanced human atheroma. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2814–2818. doi: 10.1073/pnas.89.7.2814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schrader J. W., Moyer C., Ziltener H. J., Reinisch C. L. Release of the cytokines colony-stimulating factor-1, granulocyte-macrophage colony-stimulating factor, and IL-6 by cloned murine vascular smooth muscle cells. J Immunol. 1991 Jun 1;146(11):3799–3808. [PubMed] [Google Scholar]
  36. Sieff C. A., Niemeyer C. M., Mentzer S. J., Faller D. V. Interleukin-1, tumor necrosis factor, and the production of colony-stimulating factors by cultured mesenchymal cells. Blood. 1988 Oct;72(4):1316–1323. [PubMed] [Google Scholar]
  37. Smith J. D., Trogan E., Ginsberg M., Grigaux C., Tian J., Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8264–8268. doi: 10.1073/pnas.92.18.8264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stanley E., Lieschke G. J., Grail D., Metcalf D., Hodgson G., Gall J. A., Maher D. W., Cebon J., Sinickas V., Dunn A. R. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5592–5596. doi: 10.1073/pnas.91.12.5592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  40. Sudo T., Nishikawa S., Ogawa M., Kataoka H., Ohno N., Izawa A., Hayashi S., Nishikawa S. Functional hierarchy of c-kit and c-fms in intramarrow production of CFU-M. Oncogene. 1995 Dec 21;11(12):2469–2476. [PubMed] [Google Scholar]
  41. Tushinski R. J., Stanley E. R. The regulation of mononuclear phagocyte entry into S phase by the colony stimulating factor CSF-1. J Cell Physiol. 1985 Feb;122(2):221–228. doi: 10.1002/jcp.1041220210. [DOI] [PubMed] [Google Scholar]
  42. Vairo G., Argyriou S., Bordun A. M., Whitty G., Hamilton J. A. Inhibition of the signaling pathways for macrophage proliferation by cyclic AMP. Lack of effect on early responses to colony stimulating factor-1. J Biol Chem. 1990 Feb 15;265(5):2692–2701. [PubMed] [Google Scholar]
  43. Vairo G., Hamilton J. A. Activation and proliferation signals in murine macrophages: stimulation of Na+,K+-ATPase activity by hemopoietic growth factors and other agents. J Cell Physiol. 1988 Jan;134(1):13–24. doi: 10.1002/jcp.1041340103. [DOI] [PubMed] [Google Scholar]
  44. Vairo G., Hamilton J. A. CSF-1 stimulates Na+K+-ATPase mediated 86Rb+ uptake in mouse bone marrow-derived macrophages. Biochem Biophys Res Commun. 1985 Oct 15;132(1):430–437. doi: 10.1016/0006-291x(85)91040-x. [DOI] [PubMed] [Google Scholar]
  45. Villaschi S., Spagnoli L. G. Autoradiographic and ultrastructural studies on the human fibro-atheromatous plaque. Atherosclerosis. 1983 Jul;48(1):95–100. doi: 10.1016/0021-9150(83)90020-5. [DOI] [PubMed] [Google Scholar]
  46. Wang J., Wang S., Lu Y., Weng Y., Gown A. M. GM-CSF and M-CSF expression is associated with macrophage proliferation in progressing and regressing rabbit atheromatous lesions. Exp Mol Pathol. 1994 Oct;61(2):109–118. doi: 10.1006/exmp.1994.1030. [DOI] [PubMed] [Google Scholar]
  47. Wilson N. J., Jaworowski A., Ward A. C., Hamilton J. A. cAMP enhances CSF-1-induced ERK activity and c-fos mRNA expression via a MEK-dependent and Ras-independent mechanism in macrophages. Biochem Biophys Res Commun. 1998 Mar 17;244(2):475–480. doi: 10.1006/bbrc.1998.8290. [DOI] [PubMed] [Google Scholar]
  48. Yui S., Sasaki T., Miyazaki A., Horiuchi S., Yamazaki M. Induction of murine macrophage growth by modified LDLs. Arterioscler Thromb. 1993 Mar;13(3):331–337. doi: 10.1161/01.atv.13.3.331. [DOI] [PubMed] [Google Scholar]
  49. Yusoff P., Hamilton J. A., Nolan R. D., Phillips W. A. Haematopoietic colony stimulating factors CSF-1 and GM-CSF increase phosphatidylinositol 3-kinase activity in murine bone marrow-derived macrophages. Growth Factors. 1994;10(3):181–192. doi: 10.3109/08977199409000236. [DOI] [PubMed] [Google Scholar]
  50. de Villiers W. J., Fraser I. P., Hughes D. A., Doyle A. G., Gordon S. Macrophage-colony-stimulating factor selectively enhances macrophage scavenger receptor expression and function. J Exp Med. 1994 Aug 1;180(2):705–709. doi: 10.1084/jem.180.2.705. [DOI] [PMC free article] [PubMed] [Google Scholar]

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