Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Aug 1;148(2):466–477. doi: 10.1084/jem.148.2.466

Control of the acute phase response. Demonstration of C-reactive protein synthesis and secretion by hepatocytes during acute inflammation in the rabbit

PMCID: PMC2184945  PMID: 702046

Abstract

To determine the cell of origin of C-reactive protein (CRP) and to cast light on the mechanisms leading to the acute phase response, we used an immunoenzymatic technique to visualize this protein in livers from rabbits at intervals after intramuscular injection of turpentine. CRP was detected only in hepatocytes. 8 h after turpentine injection, CRP was demonstrated in occasional periportal hepatocytes. With time, larger numbers of positive cells were detected successively in perilobular, midlobular, and centrilobular areas. On electron microscopy, CRP was detected in rough endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER), and Golgi apparatus (GA). When colchicine was administered to inhibit cellular secretion of CRP, intensity of reaction and number of CRP-containing hepatocytes were substantially greater than without colchicine, but the sequence of intralobular distribution was similar. At peak serum response 38 h after turpentine injection, CRP could be demonstrated in most hepatocytes. Electron microscopic studies showed accumulation of CRP on membranes and lumina of RER, SER, GA, and in cytoplasmic vacuoles. These findings indicate that CRP is produced by progressively increasing numbers of hepatocytes after inflammatory stimulus and suggest that a mediator, acting initially in portal zones, is responsible for recruitment of cells to CRP production.

Full Text

The Full Text of this article is available as a PDF (2.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avrameas S., Ternynck T. Peroxidase labelled antibody and Fab conjugates with enhanced intracellular penetration. Immunochemistry. 1971 Dec;8(12):1175–1179. doi: 10.1016/0019-2791(71)90395-8. [DOI] [PubMed] [Google Scholar]
  2. Avrameas S., Ternynck T. The cross-linking of proteins with glutaraldehyde and its use for the preparation of immunoadsorbents. Immunochemistry. 1969 Jan;6(1):53–66. doi: 10.1016/0019-2791(69)90178-5. [DOI] [PubMed] [Google Scholar]
  3. Bailey P. T., Abeles F. B., Hauer E. C., Mapes C. A. Intracerebroventricular administration of leukocytic endogenous mediators (LEM) in the rat. Proc Soc Exp Biol Med. 1976 Dec;153(3):419–423. doi: 10.3181/00379727-153-39560. [DOI] [PubMed] [Google Scholar]
  4. Claus D. R., Siegel J., Petras K., Osmand A. P., Gewurz H. Interactions of C-reactive protein with the first component of human complement. J Immunol. 1977 Jul;119(1):187–192. [PubMed] [Google Scholar]
  5. Feldmann G., Maurice M., Sapin C., Benhamou J. P. Inhibition by colchicine of fibrinogen translocation in hepatocytes. J Cell Biol. 1975 Oct;67(1):237–243. doi: 10.1083/jcb.67.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Graham R. C., Jr, Karnovsky M. J. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: ultrastructural cytochemistry by a new technique. J Histochem Cytochem. 1966 Apr;14(4):291–302. doi: 10.1177/14.4.291. [DOI] [PubMed] [Google Scholar]
  7. Hurlimann J., Thorbecke G. J., Hochwald G. M. The liver as the site of C-reactive protein formation. J Exp Med. 1966 Feb 1;123(2):365–378. doi: 10.1084/jem.123.2.365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. KUSHNER I., KAPLAN M. H. Studies of acute phase protein. I. An immunohistochemical method for the localization of Cx-reactive protein in rabbits. Association with necrosis in local inflammatory lesions. J Exp Med. 1961 Dec 1;114:961–974. doi: 10.1084/jem.114.6.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kaplan M. H., Volanakis J. E. Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. J Immunol. 1974 Jun;112(6):2135–2147. [PubMed] [Google Scholar]
  10. Kushner I., Broder M. L., Karp D. Control of the acute phase response. Serum C-reactive protein kinetics after acute myocardial infarction. J Clin Invest. 1978 Feb;61(2):235–242. doi: 10.1172/JCI108932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kushner I., Somerville-Volanakis J. Molecular size of rabbit C-reactive protein synthesized in vitro. J Lab Clin Med. 1976 Apr;87(4):617–623. [PubMed] [Google Scholar]
  12. Kushner I., Somerville J. A. Estimation of the molecular size of C-reactive protein and CX-reactive protein in serum. Biochim Biophys Acta. 1970 Apr 28;207(1):105–114. doi: 10.1016/0005-2795(70)90140-6. [DOI] [PubMed] [Google Scholar]
  13. Le Marchand Y., Singh A., Assimacopoulos-Jeannet F., Orci L., Rouiller C., Jeanrenaud B. A role for the microtubular system in the release of very low density lipoproteins by perfused mouse livers. J Biol Chem. 1973 Oct 10;248(19):6862–6870. [PubMed] [Google Scholar]
  14. Ma M. H., Biempica L. The normal human liver cell. Cytochemical and ultrastructural studies. Am J Pathol. 1971 Mar;62(3):353–390. [PMC free article] [PubMed] [Google Scholar]
  15. Macleod C. M., Avery O. T. THE OCCURRENCE DURING ACUTE INFECTIONS OF A PROTEIN NOT NORMALLY PRESENT IN THE BLOOD : III. IMMUNOLOGICAL PROPERTIES OF THE C-REACTIVE PROTEIN AND ITS DIFFERENTIATION FROM NORMAL BLOOD PROTEINS. J Exp Med. 1941 Jan 31;73(2):191–200. doi: 10.1084/jem.73.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Marder R. J., Fiedel B. A., Osmand A. P., Gewurz H. Inhibition of rabbit platelet aggregation and clot retraction by rabbit and human c-reactive proteins. Proc Soc Exp Biol Med. 1977 May;155(1):44–47. doi: 10.3181/00379727-155-39741. [DOI] [PubMed] [Google Scholar]
  17. Mortensen R. F., Braun D., Gewurz H. Effects of C-reactive protein on lymphocyte functions. III. Inhibition of antigen-induced lymphocyte stimulation and lymphokine production. Cell Immunol. 1977 Jan;28(1):59–68. doi: 10.1016/s0008-8749(77)80006-3. [DOI] [PubMed] [Google Scholar]
  18. Osmand A. P., Friedenson B., Gewurz H., Painter R. H., Hofmann T., Shelton E. Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins). Proc Natl Acad Sci U S A. 1977 Feb;74(2):739–743. doi: 10.1073/pnas.74.2.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Palade G. Intracellular aspects of the process of protein synthesis. Science. 1975 Aug 1;189(4200):347–358. doi: 10.1126/science.1096303. [DOI] [PubMed] [Google Scholar]
  20. RAPPAPORT A. M., BOROWY Z. J., LOUGHEED W. M., LOTTO W. N. Subdivision of hexagonal liver lobules into a structural and functional unit; role in hepatic physiology and pathology. Anat Rec. 1954 May;119(1):11–33. doi: 10.1002/ar.1091190103. [DOI] [PubMed] [Google Scholar]
  21. Redman C. M., Banerjee D., Howell K., Palade G. E. Colchicine inhibition of plasma protein release from rat hepatocytes. J Cell Biol. 1975 Jul;66(1):42–59. doi: 10.1083/jcb.66.1.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Riley R. F., Coleman M. K. Isolation of C-reactive proteins of man, monkey, rabbit and dog by affinity chromatography on phosphorylated cellulose. Clin Chim Acta. 1970 Nov;30(2):483–496. doi: 10.1016/0009-8981(70)90141-5. [DOI] [PubMed] [Google Scholar]
  23. SHANK R. E., MORRISON G., CHENG C. H., KARL I., SCHWARTZ R. Cell heterogeneity within the hepatic lobule: quantitative histochemistry. J Histochem Cytochem. 1959 Jul;7(4):237–239. doi: 10.1177/7.4.237. [DOI] [PubMed] [Google Scholar]
  24. Stein O., Sanger L., Stein Y. Colchicine-induced inhibition of lipoprotein and protein secretion into the serum and lack of interference with secretion of biliary phospholipids and cholesterol by rat liver in vivo. J Cell Biol. 1974 Jul;62(1):90–103. doi: 10.1083/jcb.62.1.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yen-Watson B., Kushner I. Rabbit CRP response to endotoxin administration: dose-response relationship and kinetics. Proc Soc Exp Biol Med. 1974 Sep;146(4):1132–1136. doi: 10.3181/00379727-146-38260. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES