Skip to main content

Study of the interaction of the C-reactive protein monomer with the U937 monocyte


C-reactive protein (CRP) has two structurally distinct isoforms, the CRP pentamer and the CRP monomer. A role for the CRP monomer in atherosclerosis is emerging, but the underlying mechanisms are only beginning to be understood. Monocytes are an important contributor to atherosclerosis, and foam cell formation is the hallmark of atherogenesis. However, whether the CRP monomer can directly interact with the monocytes and modulate their responses remains unknown. Furthermore, although FcγRIII (CD16) has been identified as the receptor for the CRP monomer on neutrophils, its role in mediating the CRP monomer’s biological effects in other cell types has been questioned. In this study, we investigated the interaction of the CRP monomer with the monocytes using the U937 monocytic cell line. The CRP monomer specifically binds to U937 cells. This binding is unique in that it is independent of FcγRs and insensitive to protease digestion of the cell surface proteins. Further assays revealed that the CRP monomer directly incorporates into the plasma membrane. Interestingly, the presence of the CRP monomer efficiently retards oxidized low-density lipoprotein-induced foam cell formation of PMA-differentiated U937 macrophages and peripheral blood monocytic cell-derived macrophages. These findings provide additional evidence for the notion that the CRP monomer is an active CRP isoform that plays a role in atherogenesis via the direct modulation of the behavior of the monocytes.



C-reactive protein


Fc gamma receptor


low-density lipoprotein


oxidized low-density lipoprotein


peripheral blood monocytic cell


thiobarbituric acid reactive substances


  1. Pepys, M.B. and Hirschfield, G.M. C-reactive protein: a critical update. J. Clin. Invest. 111 (2003) 1805–1812.

    CAS  PubMed  Google Scholar 

  2. Boncler, M. and Watala, C. Regulation of cell function by isoforms of C-reactive protein: a comparative analysis. Acta Biochim. Pol. 56 (2009) 17–31.

    CAS  PubMed  Google Scholar 

  3. Schwedler, S.B., Filep, J.G., Galle, J., Wanner, C. and Potempa, L.A. C-reactive protein: a family of proteins to regulate cardiovascular function. Am. J. Kidney Dis. 47 (2006) 212–222.

    Article  CAS  PubMed  Google Scholar 

  4. Verma, S., Devaraj, S. and Jialal, I. C-reactive protein promotes atherothrombosis. Circulation 113 (2006) 2135–2151.

    PubMed  Google Scholar 

  5. Casas, J.P., Shah, T., Hingorani, A.D., Danesh, J. and Pepys, M.B. C-reactive protein and coronary heart disease: a critical review. J. Intern. Med. 264 (2008) 295–314.

    Article  CAS  PubMed  Google Scholar 

  6. Ji, S.R., Wu, Y., Zhu, L., Potempa, L.A., Sheng, F.L., Lu, W. and Zhao, J. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J. 21 (2007) 284–294.

    Article  CAS  PubMed  Google Scholar 

  7. Khreiss, T., Jozsef, L., Potempa, L.A. and Filep, J.G. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 109 (2004) 2016–2022.

    Article  CAS  PubMed  Google Scholar 

  8. Molins, B., Pena, E., Vilahur, G., Mendieta, C., Slevin, M. and Badimon, L. C-Reactive Protein Isoforms Differ in Their Effects on Thrombus Growth. Arterioscler. Thromb. Vasc. Biol. 28 (2008) 2239–2246.

    Article  CAS  PubMed  Google Scholar 

  9. Khreiss, T., Jozsef, L., Potempa, L.A. and Filep, J.G. Opposing effects of C-reactive protein isoforms on shear-induced neutrophil-platelet adhesion and neutrophil aggregation in whole blood. Circulation 110 (2004) 2713–2720.

    Article  CAS  PubMed  Google Scholar 

  10. Khreiss, T., Jozsef, L., Potempa, L.A. and Filep, J.G. Loss of pentameric symmetry in C-reactive protein induces interleukin-8 secretion through peroxynitrite signaling in human neutrophils. Circ. Res. 97 (2005) 690–697.

    Article  CAS  PubMed  Google Scholar 

  11. Khreiss, T., Jozsef, L., Hossain, S., Chan, J.S., Potempa, L.A. and Filep, J.G. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J. Biol. Chem. 277 (2002) 40775–40781.

    Article  CAS  PubMed  Google Scholar 

  12. Li, A.C. and Glass, C.K. The macrophage foam cell as a target for therapeutic intervention. Nat. Med. 8 (2002) 1235–1242.

    Article  CAS  PubMed  Google Scholar 

  13. Heuertz, R.M., Schneider, G.P., Potempa, L.A. and Webster, R.O. Native and modified C-reactive protein bind different receptors on human neutrophils. Int. J. Biochem. Cell Biol. 37 (2005) 320–335.

    Article  CAS  PubMed  Google Scholar 

  14. Potempa, L.A., Maldonado, B.A., Laurent, P., Zemel, E.S. and Gewurz, H. Antigenic, electrophoretic and binding alterations of human C-reactive protein modified selectively in the absence of calcium. Mol. Immunol. 20 (1983) 1165–1175.

    Article  CAS  PubMed  Google Scholar 

  15. Taskinen, S., Kovanen, P.T., Jarva, H., Meri, S. and Pentikainen, M.O. Binding of C-reactive protein to modified low-density-lipoprotein particles: identification of cholesterol as a novel ligand for C-reactive protein. Biochem. J. 367 (2002) 403–412.

    Article  CAS  PubMed  Google Scholar 

  16. Nagano, Y., Arai, H. and Kita, T. High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cell after oxidative modification. Proc. Natl. Acad. Sci. USA 88 (1991) 6457–6461.

    Article  CAS  PubMed  Google Scholar 

  17. Olsson, U., Camejo, G., Hurt-Camejo, E., Elfsber, K., Wiklund, O. and Bondjers, G. Possible functional interactions of apolipoprotein B-100 segments that associate with cell proteoglycans and the ApoB/E receptor. Arterioscler. Thromb. Vasc. Biol. 17 (1997) 149–155.

    CAS  PubMed  Google Scholar 

  18. Bickel, P.E., Scherer, P.E., Schnitzer, J.E., Oh, P., Lisanti, M.P. and Lodish, H.F. Flotillin and epidermal surface antigen define a new family of caveolae-associated integral membrane proteins. J. Biol. Chem. 272 (1997) 13793–13802.

    Article  CAS  PubMed  Google Scholar 

  19. Fu, T. and Borensztajn, J. Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions. Biochem. J. 366 (2002) 195–201.

    CAS  PubMed  Google Scholar 

  20. Greenspan, P., Mayer, E.P. and Fowler, S.D. Nile red: a selective fluorescent stain for intracellular lipid droplets. J. Cell Biol. 100 (1985) 965–973.

    Article  CAS  PubMed  Google Scholar 

  21. Ryu, J., Lee, C.W., Shin, J.A., Park, C.S., Kim, J.J., Park, S.J. and Han, K.H. FcgammaRIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4. Cardiovasc. Res. 75 (2007) 555–565.

    Article  CAS  PubMed  Google Scholar 

  22. Looney, R.J., Abraham, G.N. and Anderson, C.L. Human monocytes and U937 cells bear two distinct Fc receptors for IgG. J. Immunol. 136 (1986) 1641–1647.

    CAS  PubMed  Google Scholar 

  23. Bharadwaj, D., Stein, M.P., Volzer, M., Mold, C. and Du Clos, T.W. The major receptor for C-reactive protein on leukocytes is fcgamma receptor II. J. Exp. Med. 190 (1999) 585–590.

    Article  CAS  PubMed  Google Scholar 

  24. Crowell, R.E., Du Clos, T.W., Montoya, G., Heaphy, E. and Mold, C. C-reactive protein receptors on the human monocytic cell line U-937. Evidence for additional binding to Fc gamma RI. J. Immunol. 147 (1991) 3445–3451.

    CAS  PubMed  Google Scholar 

  25. Ji, S.R., Ma, L., Bai C.J., Shi, J.M., Li, H.Y., Potempa, L.A., Filep, J.G., Zhao, J. and Wu, Y. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft micro-domains. FASEB J. 23 (2009) 1806–1816.

    Article  CAS  PubMed  Google Scholar 

  26. Eisenhardt, S.U., Habersberger, J., Murphy, A., Chen, Y.C., Woollard, K.J., Bassler, N., Qian, H., von Zur Muhlen, C., Hagemeyer, C.E., Ahrens, I., Chin-Dusting, J., Bobik, A. and Peter, K. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ. Res. 105 (2009) 128–137.

    Article  CAS  PubMed  Google Scholar 

  27. Singh, S.K., Suresh, M.V., Prayther, D.C., Moorman, J.P., Rusinol, A.E. and Agrawal, A. C-reactive protein-bound enzymatically modified low-density lipoprotein does not transform macrophages into foam cells. J. Immunol. 180 (2008) 4316–4322.

    CAS  PubMed  Google Scholar 

  28. Ji, S.R., Wu, Y., Potempa, L.A., Liang, Y.H. and Zhao, J. Effect of modified C-reactive protein on complement Activation. A possible complement regulatory role of modified or monomeric C-reactive protein in atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 26 (2006) 935–941.

    Article  CAS  PubMed  Google Scholar 

  29. Schwedler, S.B., Amann, K., Wernicke, K., Krebs, A., Nauck, M., Wanner, C., Potempa, L.A. and Galle, J. Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation 112 (2005) 1016–1023.

    Article  CAS  PubMed  Google Scholar 

  30. Ji, S.R., Wu, Y., Potempa, L.A., Qiu, Q. and Zhao, J. Interactions of C-reactive protein with low density lipoproteins: implications for an active role of modified C-reactive protein in atherosclerosis. Int. J. Biochem. Cell Biol. 38 (2006) 648–661.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Xin-He Shi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhao, J., Shi, XH. Study of the interaction of the C-reactive protein monomer with the U937 monocyte. Cell Mol Biol Lett 15, 485–495 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Key words

  • C-reactive protein
  • Monocyte
  • Low-density lipoprotein
  • Foam cell