Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Sep 1;178(3):1017–1022. doi: 10.1084/jem.178.3.1017

Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages

PMCID: PMC2191180  PMID: 8350043

Abstract

The hematopoietic cell kinase (hck) is a member of the src family of tyrosine kinases, and is primarily expressed in myeloid cells. Hck expression increases with terminal differentiation in both monocyte/macrophages and granulocytes and is further augmented during macrophage activation. Recent evidence has implicated src-related tyrosine kinases in critical signaling pathways in other hematopoietic lineages. Herein we demonstrate that manipulation of the level of hck expression in the murine macrophage cell line BAC1.2F5 alters the responsiveness of these cells to activation by bacterial lipopolysaccharide (LPS) but does not affect survival or proliferation. Overexpression of an activated mutant of hck in BAC1.2F5 cells augments tumor necrosis factor (TNF) production in response to LPS, whereas inhibition of endogenous hck expression, by antisense oligonucleotides, interferes with LPS-mediated TNF synthesis. Together, these observations suggest that hck is an important component of the signal transduction pathways in activated macrophages.

Full Text

The Full Text of this article is available as a PDF (820.3 KB).

Selected References

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

  1. Adams D. O., Hamilton T. A. The cell biology of macrophage activation. Annu Rev Immunol. 1984;2:283–318. doi: 10.1146/annurev.iy.02.040184.001435. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  3. Boulet I., Ralph S., Stanley E., Lock P., Dunn A. R., Green S. P., Phillips W. A. Lipopolysaccharide- and interferon-gamma-induced expression of hck and lyn tyrosine kinases in murine bone marrow-derived macrophages. Oncogene. 1992 Apr;7(4):703–710. [PubMed] [Google Scholar]
  4. Boyle W. J., van der Geer P., Hunter T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 1991;201:110–149. doi: 10.1016/0076-6879(91)01013-r. [DOI] [PubMed] [Google Scholar]
  5. Burchett S. K., Weaver W. M., Westall J. A., Larsen A., Kronheim S., Wilson C. B. Regulation of tumor necrosis factor/cachectin and IL-1 secretion in human mononuclear phagocytes. J Immunol. 1988 May 15;140(10):3473–3481. [PubMed] [Google Scholar]
  6. Cooke M. P., Abraham K. M., Forbush K. A., Perlmutter R. M. Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991 Apr 19;65(2):281–291. doi: 10.1016/0092-8674(91)90162-r. [DOI] [PubMed] [Google Scholar]
  7. Cooper J. A., Esch F. S., Taylor S. S., Hunter T. Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro. J Biol Chem. 1984 Jun 25;259(12):7835–7841. [PubMed] [Google Scholar]
  8. Davidson D., Chow L. M., Fournel M., Veillette A. Differential regulation of T cell antigen responsiveness by isoforms of the src-related tyrosine protein kinase p59fyn. J Exp Med. 1992 Jun 1;175(6):1483–1492. doi: 10.1084/jem.175.6.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eiseman E., Bolen J. B. src-related tyrosine protein kinases as signaling components in hematopoietic cells. Cancer Cells. 1990 Oct;2(10):303–310. [PubMed] [Google Scholar]
  10. Holtzman D. A., Cook W. D., Dunn A. R. Isolation and sequence of a cDNA corresponding to a src-related gene expressed in murine hemopoietic cells. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8325–8329. doi: 10.1073/pnas.84.23.8325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kmiecik T. E., Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987 Apr 10;49(1):65–73. doi: 10.1016/0092-8674(87)90756-2. [DOI] [PubMed] [Google Scholar]
  12. Lewis D. B., Larsen A., Wilson C. B. Reduced interferon-gamma mRNA levels in human neonates. Evidence for an intrinsic T cell deficiency independent of other genes involved in T cell activation. J Exp Med. 1986 Apr 1;163(4):1018–1023. doi: 10.1084/jem.163.4.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lichtenberg U., Quintrell N., Bishop J. M. Human protein-tyrosine kinase gene HCK: expression and structural analysis of the promoter region. Oncogene. 1992 May;7(5):849–858. [PubMed] [Google Scholar]
  14. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  15. Marth J. D., Lewis D. B., Cooke M. P., Mellins E. D., Gearn M. E., Samelson L. E., Wilson C. B., Miller A. D., Perlmutter R. M. Lymphocyte activation provokes modification of a lymphocyte-specific protein tyrosine kinase (p56lck). J Immunol. 1989 Apr 1;142(7):2430–2437. [PubMed] [Google Scholar]
  16. Morgan C., Pollard J. W., Stanley E. R. Isolation and characterization of a cloned growth factor dependent macrophage cell line, BAC1.2F5. J Cell Physiol. 1987 Mar;130(3):420–427. doi: 10.1002/jcp.1041300316. [DOI] [PubMed] [Google Scholar]
  17. Perlmutter R. M., Marth J. D., Ziegler S. F., Garvin A. M., Pawar S., Cooke M. P., Abraham K. M. Specialized protein tyrosine kinase proto-oncogenes in hematopoietic cells. Biochim Biophys Acta. 1989 Feb;948(3):245–262. doi: 10.1016/0304-419x(89)90001-2. [DOI] [PubMed] [Google Scholar]
  18. Quintrell N., Lebo R., Varmus H., Bishop J. M., Pettenati M. J., Le Beau M. M., Diaz M. O., Rowley J. D. Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol Cell Biol. 1987 Jun;7(6):2267–2275. doi: 10.1128/mcb.7.6.2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Samelson L. E., Phillips A. F., Luong E. T., Klausner R. D. Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4358–4362. doi: 10.1073/pnas.87.11.4358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schwarzbaum S., Halpern R., Diamond B. The generation of macrophage-like cell lines by transfection with SV40 origin defective DNA. J Immunol. 1984 Mar;132(3):1158–1162. [PubMed] [Google Scholar]
  21. Shaw A. S., Amrein K. E., Hammond C., Stern D. F., Sefton B. M., Rose J. K. The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell. 1989 Nov 17;59(4):627–636. doi: 10.1016/0092-8674(89)90008-1. [DOI] [PubMed] [Google Scholar]
  22. Stanley E. R., Heard P. M. Factors regulating macrophage production and growth. Purification and some properties of the colony stimulating factor from medium conditioned by mouse L cells. J Biol Chem. 1977 Jun 25;252(12):4305–4312. [PubMed] [Google Scholar]
  23. Turner J. M., Brodsky M. H., Irving B. A., Levin S. D., Perlmutter R. M., Littman D. R. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990 Mar 9;60(5):755–765. doi: 10.1016/0092-8674(90)90090-2. [DOI] [PubMed] [Google Scholar]
  24. Veillette A., Bookman M. A., Horak E. M., Bolen J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. doi: 10.1016/0092-8674(88)90053-0. [DOI] [PubMed] [Google Scholar]
  25. Veillette A., Bookman M. A., Horak E. M., Samelson L. E., Bolen J. B. Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature. 1989 Mar 16;338(6212):257–259. doi: 10.1038/338257a0. [DOI] [PubMed] [Google Scholar]
  26. Weinstein S. L., Gold M. R., DeFranco A. L. Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4148–4152. doi: 10.1073/pnas.88.10.4148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wheeler E. F., Rettenmier C. W., Look A. T., Sherr C. J. The v-fms oncogene induces factor independence and tumorigenicity in CSF-1 dependent macrophage cell line. 1986 Nov 27-Dec 3Nature. 324(6095):377–380. doi: 10.1038/324377a0. [DOI] [PubMed] [Google Scholar]
  28. Yamanashi Y., Kakiuchi T., Mizuguchi J., Yamamoto T., Toyoshima K. Association of B cell antigen receptor with protein tyrosine kinase Lyn. Science. 1991 Jan 11;251(4990):192–194. doi: 10.1126/science.1702903. [DOI] [PubMed] [Google Scholar]
  29. Yi T. L., Bolen J. B., Ihle J. N. Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus. Mol Cell Biol. 1991 May;11(5):2391–2398. doi: 10.1128/mcb.11.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Yi T. L., Willman C. L. Cloning of the murine c-fgr proto-oncogene cDNA and induction of c-fgr expression by proliferation and activation factors in normal bone marrow-derived monocytic cells. Oncogene. 1989 Sep;4(9):1081–1087. [PubMed] [Google Scholar]
  31. Ziegler S. F., Levin S. D., Perlmutter R. M. Transformation of NIH 3T3 fibroblasts by an activated form of p59hck. Mol Cell Biol. 1989 Jun;9(6):2724–2727. doi: 10.1128/mcb.9.6.2724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ziegler S. F., Marth J. D., Lewis D. B., Perlmutter R. M. Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Mol Cell Biol. 1987 Jun;7(6):2276–2285. doi: 10.1128/mcb.7.6.2276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ziegler S. F., Wilson C. B., Perlmutter R. M. Augmented expression of a myeloid-specific protein tyrosine kinase gene (hck) after macrophage activation. J Exp Med. 1988 Nov 1;168(5):1801–1810. doi: 10.1084/jem.168.5.1801. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES