Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1995 Oct;63(10):3871–3877. doi: 10.1128/iai.63.10.3871-3877.1995

Chemokine response in mice infected with Mycobacterium tuberculosis.

E R Rhoades 1, A M Cooper 1, I M Orme 1
PMCID: PMC173545  PMID: 7558294

Abstract

We show here that infection of murine macrophages with various strains of Mycobacterium tuberculosis induces the rapid in vitro expression of genes encoding chemokines macrophage inflammatory protein 1 alpha and macrophage inflammatory protein 2, which recruit neutrophils to sites of infection, and macrophage-recruiting chemokines 10-kDa, interferon-inducible protein (IP-10) and macrophage chemotactic protein 1. Three strains of M. tuberculosis, Erdman and the clinical isolates CSU 22 and CSU 46, induced similar levels of secretion of macrophage chemotactic protein 1 from infected macrophage monolayers; however, the Erdman strain failed to induce levels of secretion of tumor necrosis factor alpha similar to those induced by either CSU 22 or CSU 46. Using a low-dose aerosol infection model, we also found that while the Erdman strain induced negligible increases in chemokine mRNA levels in the lungs, infection with either CSU 22 or CSU 46 resulted in greater levels of mRNA production for all four chemokines tested. The growth of these strains in the lungs was, however, equally well contained by acquired host immunity. These data allow us to hypothesize that the chemokine response in the lungs probably does not control the protective granulomatous response and that perhaps other T-cell- or macrophage-associated cytokines such as tumor necrosis factor alpha or interleukin 12 may be involved in this process.

Full Text

The Full Text of this article is available as a PDF (305.7 KB).

Selected References

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

  1. Adler K. B., Fischer B. M., Wright D. T., Cohn L. A., Becker S. Interactions between respiratory epithelial cells and cytokines: relationships to lung inflammation. Ann N Y Acad Sci. 1994 May 28;725:128–145. doi: 10.1111/j.1749-6632.1994.tb00275.x. [DOI] [PubMed] [Google Scholar]
  2. Appelberg R. Macrophage inflammatory proteins MIP-1 and MIP-2 are involved in T cell-mediated neutrophil recruitment. J Leukoc Biol. 1992 Sep;52(3):303–306. doi: 10.1002/jlb.52.3.303. [DOI] [PubMed] [Google Scholar]
  3. Barnes P. F., Abrams J. S., Lu S., Sieling P. A., Rea T. H., Modlin R. L. Patterns of cytokine production by mycobacterium-reactive human T-cell clones. Infect Immun. 1993 Jan;61(1):197–203. doi: 10.1128/iai.61.1.197-203.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bermudez L. E. Production of transforming growth factor-beta by Mycobacterium avium-infected human macrophages is associated with unresponsiveness to IFN-gamma. J Immunol. 1993 Mar 1;150(5):1838–1845. [PubMed] [Google Scholar]
  5. Cooper A. M., Roberts A. D., Rhoades E. R., Callahan J. E., Getzy D. M., Orme I. M. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PMC free article] [PubMed] [Google Scholar]
  6. Dewald B., Moser B., Barella L., Schumacher C., Baggiolini M., Clark-Lewis I. IP-10, a gamma-interferon-inducible protein related to interleukin-8, lacks neutrophil activating properties. Immunol Lett. 1992 Mar;32(1):81–84. doi: 10.1016/0165-2478(92)90203-z. [DOI] [PubMed] [Google Scholar]
  7. Fahey T. J., 3rd, Tracey K. J., Tekamp-Olson P., Cousens L. S., Jones W. G., Shires G. T., Cerami A., Sherry B. Macrophage inflammatory protein 1 modulates macrophage function. J Immunol. 1992 May 1;148(9):2764–2769. [PubMed] [Google Scholar]
  8. Friedland J. S. Chemotactic cytokines and tuberculosis. Biochem Soc Trans. 1994 May;22(2):310–312. doi: 10.1042/bst0220310. [DOI] [PubMed] [Google Scholar]
  9. Friedland J. S., Remick D. G., Shattock R., Griffin G. E. Secretion of interleukin-8 following phagocytosis of Mycobacterium tuberculosis by human monocyte cell lines. Eur J Immunol. 1992 Jun;22(6):1373–1378. doi: 10.1002/eji.1830220607. [DOI] [PubMed] [Google Scholar]
  10. Han J., Brown T., Beutler B. Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level. J Exp Med. 1990 Feb 1;171(2):465–475. doi: 10.1084/jem.171.2.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kaplan G., Luster A. D., Hancock G., Cohn Z. A. The expression of a gamma interferon-induced protein (IP-10) in delayed immune responses in human skin. J Exp Med. 1987 Oct 1;166(4):1098–1108. doi: 10.1084/jem.166.4.1098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. doi: 10.1164/ajrccm/141.3.765. [DOI] [PubMed] [Google Scholar]
  13. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  14. Kruys V., Beutler B., Huez G. Translational control mediated by UA-rich sequences. Enzyme. 1990;44(1-4):193–202. doi: 10.1159/000468757. [DOI] [PubMed] [Google Scholar]
  15. Kruys V., Marinx O., Shaw G., Deschamps J., Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science. 1989 Aug 25;245(4920):852–855. doi: 10.1126/science.2672333. [DOI] [PubMed] [Google Scholar]
  16. Kunkel S. L., Lukacs N. W., Strieter R. M. The role of interleukin-8 in the infectious process. Ann N Y Acad Sci. 1994 Aug 15;730:134–143. doi: 10.1111/j.1749-6632.1994.tb44245.x. [DOI] [PubMed] [Google Scholar]
  17. Larrick J. W., Kunkel S. L. The role of tumor necrosis factor and interleukin 1 in the immunoinflammatory response. Pharm Res. 1988 Mar;5(3):129–139. doi: 10.1023/a:1015904721223. [DOI] [PubMed] [Google Scholar]
  18. Larsen C. G., Zachariae C. O., Oppenheim J. J., Matsushima K. Production of monocyte chemotactic and activating factor (MCAF) by human dermal fibroblasts in response to interleukin 1 or tumor necrosis factor. Biochem Biophys Res Commun. 1989 May 15;160(3):1403–1408. doi: 10.1016/s0006-291x(89)80160-3. [DOI] [PubMed] [Google Scholar]
  19. Leonard E. J., Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today. 1990 Mar;11(3):97–101. doi: 10.1016/0167-5699(90)90035-8. [DOI] [PubMed] [Google Scholar]
  20. Lieberman A. P., Pitha P. M., Shin M. L. Poly(A) removal is the kinase-regulated step in tumor necrosis factor mRNA decay. J Biol Chem. 1992 Feb 5;267(4):2123–2126. [PubMed] [Google Scholar]
  21. Matsushima K., Morishita K., Yoshimura T., Lavu S., Kobayashi Y., Lew W., Appella E., Kung H. F., Leonard E. J., Oppenheim J. J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med. 1988 Jun 1;167(6):1883–1893. doi: 10.1084/jem.167.6.1883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohmori Y., Hamilton T. A. A macrophage LPS-inducible early gene encodes the murine homologue of IP-10. Biochem Biophys Res Commun. 1990 May 16;168(3):1261–1267. doi: 10.1016/0006-291x(90)91164-n. [DOI] [PubMed] [Google Scholar]
  23. Oppenheim J. J., Zachariae C. O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. doi: 10.1146/annurev.iy.09.040191.003153. [DOI] [PubMed] [Google Scholar]
  24. Ordway D. J., Sonnenberg M. G., Donahue S. A., Belisle J. T., Orme I. M. Drug-resistant strains of Mycobacterium tuberculosis exhibit a range of virulence for mice. Infect Immun. 1995 Feb;63(2):741–743. doi: 10.1128/iai.63.2.741-743.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Orme I. M., Andersen P., Boom W. H. T cell response to Mycobacterium tuberculosis. J Infect Dis. 1993 Jun;167(6):1481–1497. doi: 10.1093/infdis/167.6.1481. [DOI] [PubMed] [Google Scholar]
  26. Orme I. M., Roberts A. D., Griffin J. P., Abrams J. S. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. J Immunol. 1993 Jul 1;151(1):518–525. [PubMed] [Google Scholar]
  27. Rastogi N., Bachelet M., Carvalho de Sousa J. P. Intracellular growth of Mycobacterium avium in human macrophages is linked to the increased synthesis of prostaglandin E2 and inhibition of the phagosome-lysosome fusions. FEMS Microbiol Immunol. 1992 Jul;4(5):273–279. doi: 10.1111/j.1574-6968.1992.tb05006.x. [DOI] [PubMed] [Google Scholar]
  28. Rollins B. J., Morrison E. D., Stiles C. D. Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3738–3742. doi: 10.1073/pnas.85.11.3738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sherry B., Tekamp-Olson P., Gallegos C., Bauer D., Davatelis G., Wolpe S. D., Masiarz F., Coit D., Cerami A. Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta. J Exp Med. 1988 Dec 1;168(6):2251–2259. doi: 10.1084/jem.168.6.2251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shiratsuchi H., Johnson J. L., Ellner J. J. Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol. 1991 May 1;146(9):3165–3170. [PubMed] [Google Scholar]
  31. Shiratsuchi H., Toossi Z., Mettler M. A., Ellner J. J. Colonial morphotype as a determinant of cytokine expression by human monocytes infected with Mycobacterium avium. J Immunol. 1993 Apr 1;150(7):2945–2954. [PubMed] [Google Scholar]
  32. Sica A., Wang J. M., Colotta F., Dejana E., Mantovani A., Oppenheim J. J., Larsen C. G., Zachariae C. O., Matsushima K. Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor. J Immunol. 1990 Apr 15;144(8):3034–3038. [PubMed] [Google Scholar]
  33. Sonouchi K., Hamilton T. A., Tannenbaum C. S., Tubbs R. R., Bukowski R., Finke J. H. Chemokine gene expression in the murine renal cell carcinoma, RENCA, following treatment in vivo with interferon-alpha and interleukin-2. Am J Pathol. 1994 Apr;144(4):747–755. [PMC free article] [PubMed] [Google Scholar]
  34. Standiford T. J., Kunkel S. L., Basha M. A., Chensue S. W., Lynch J. P., 3rd, Toews G. B., Westwick J., Strieter R. M. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990 Dec;86(6):1945–1953. doi: 10.1172/JCI114928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Standiford T. J., Kunkel S. L., Phan S. H., Rollins B. J., Strieter R. M. Alveolar macrophage-derived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II-like epithelial cells. J Biol Chem. 1991 May 25;266(15):9912–9918. [PubMed] [Google Scholar]
  36. Strieter R. M., Wiggins R., Phan S. H., Wharram B. L., Showell H. J., Remick D. G., Chensue S. W., Kunkel S. L. Monocyte chemotactic protein gene expression by cytokine-treated human fibroblasts and endothelial cells. Biochem Biophys Res Commun. 1989 Jul 31;162(2):694–700. doi: 10.1016/0006-291x(89)92366-8. [DOI] [PubMed] [Google Scholar]
  37. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  38. Tanaka Y., Adams D. H., Hubscher S., Hirano H., Siebenlist U., Shaw S. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature. 1993 Jan 7;361(6407):79–82. doi: 10.1038/361079a0. [DOI] [PubMed] [Google Scholar]
  39. Taub D. D., Conlon K., Lloyd A. R., Oppenheim J. J., Kelvin D. J. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science. 1993 Apr 16;260(5106):355–358. doi: 10.1126/science.7682337. [DOI] [PubMed] [Google Scholar]
  40. Tekamp-Olson P., Gallegos C., Bauer D., McClain J., Sherry B., Fabre M., van Deventer S., Cerami A. Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues. J Exp Med. 1990 Sep 1;172(3):911–919. doi: 10.1084/jem.172.3.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vaddi K., Newton R. C. Comparison of biological responses of human monocytes and THP-1 cells to chemokines of the intercrine-beta family. J Leukoc Biol. 1994 Jun;55(6):756–762. doi: 10.1002/jlb.55.6.756. [DOI] [PubMed] [Google Scholar]
  42. Valente A. J., Graves D. T., Vialle-Valentin C. E., Delgado R., Schwartz C. J. Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular cells in culture. Biochemistry. 1988 May 31;27(11):4162–4168. doi: 10.1021/bi00411a039. [DOI] [PubMed] [Google Scholar]
  43. Valone S. E., Rich E. A., Wallis R. S., Ellner J. J. Expression of tumor necrosis factor in vitro by human mononuclear phagocytes stimulated with whole Mycobacterium bovis BCG and mycobacterial antigens. Infect Immun. 1988 Dec;56(12):3313–3315. doi: 10.1128/iai.56.12.3313-3315.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wallis R. S., Fujiwara H., Ellner J. J. Direct stimulation of monocyte release of interleukin 1 by mycobacterial protein antigens. J Immunol. 1986 Jan;136(1):193–196. [PubMed] [Google Scholar]
  45. Watson R. W., Redmond H. P., Bouchier-Hayes D. Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses. J Leukoc Biol. 1994 Jul;56(1):95–103. doi: 10.1002/jlb.56.1.95. [DOI] [PubMed] [Google Scholar]
  46. Widmer U., Manogue K. R., Cerami A., Sherry B. Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol. 1993 Jun 1;150(11):4996–5012. [PubMed] [Google Scholar]
  47. Widmer U., Yang Z., van Deventer S., Manogue K. R., Sherry B., Cerami A. Genomic structure of murine macrophage inflammatory protein-1 alpha and conservation of potential regulatory sequences with a human homolog, LD78. J Immunol. 1991 Jun 1;146(11):4031–4040. [PubMed] [Google Scholar]
  48. Wolpe S. D., Davatelis G., Sherry B., Beutler B., Hesse D. G., Nguyen H. T., Moldawer L. L., Nathan C. F., Lowry S. F., Cerami A. Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J Exp Med. 1988 Feb 1;167(2):570–581. doi: 10.1084/jem.167.2.570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
  50. Wynn T. A., Eltoum I., Oswald I. P., Cheever A. W., Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. doi: 10.1084/jem.179.5.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Xu S., Cooper A., Sturgill-Koszycki S., van Heyningen T., Chatterjee D., Orme I., Allen P., Russell D. G. Intracellular trafficking in Mycobacterium tuberculosis and Mycobacterium avium-infected macrophages. J Immunol. 1994 Sep 15;153(6):2568–2578. [PubMed] [Google Scholar]
  52. Yoshimura T., Leonard E. J. Secretion by human fibroblasts of monocyte chemoattractant protein-1, the product of gene JE. J Immunol. 1990 Mar 15;144(6):2377–2383. [PubMed] [Google Scholar]
  53. Yoshimura T., Yuhki N., Moore S. K., Appella E., Lerman M. I., Leonard E. J. Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett. 1989 Feb 27;244(2):487–493. doi: 10.1016/0014-5793(89)80590-3. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES