Search tips
Search criteria 


Logo of iaiPermissionsJournals.ASM.orgJournalIAI ArticleJournal InfoAuthorsReviewers
Infect Immun. 1997 May; 65(5): 1793–1799.
PMCID: PMC175219

In vivo induction of apoptosis in the thymus by administration of mycobacterial cord factor (trehalose 6,6'-dimycolate).


It is reported that some bacteria or bacterial components cause thymic atrophy via the apoptotic process. The present study demonstrated for the first time in vivo induction of apoptosis in the mouse thymus by mycobacterial cord factor (CF) (trehalose 6,6'-dimycolate). When 300 microg of purified CF from Mycobacterium tuberculosis was intravenously administered to BALB/c mice in the form of water-in-oil-in-water (w/o/w) emulsion, thymic atrophy and pulmonary granulomas were induced with a peak on day 7, whereas, in the form of liposomes, CF induced thymic atrophy on days 14 to 21 in parallel with the development of hepatic granulomas. Thymic atrophy resulted from the depletion of cortical lymphocytes via apoptosis as revealed by DNA fragmentation and karyorrhectic changes. In contrast, mycobacterial sulfatide (2,3,6,6'-tetraacyl trehalose 2'-sulfate) caused neither thymic atrophy nor granuloma formation. Compared to lipopolysaccharide-induced thymocyte apoptosis, CF (w/o/w)-induced thymocyte apoptosis developed more slowly, reached a maximum later, and lasted longer but was less intense. Although serum tumor necrosis factor alpha (TNF-alpha) levels in CF-treated mice were not significantly elevated, administration of anti-TNF-alpha antibody almost completely inhibited thymic atrophy and granuloma formation. Serum corticosterone levels were only slightly elevated by CF administration. The present results indicate that mycobacterial CF induces thymic atrophy via apoptosis, which is closely linked with granuloma formation.

Full Text

The Full Text of this article is available as a PDF (932K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Abo T, Kusumi A, Seki S, Ohteki T, Sugiura K, Masuda T, Rikiishi H, Iiai T, Kumagai K. Activation of extrathymic T cells in the liver and reciprocal inactivation of intrathymic T cells by bacterial stimulation. Cell Immunol. 1992 Jun;142(1):125–136. [PubMed]
  • Asano M, Nakane A, Minagawa T. Endogenous gamma interferon is essential in granuloma formation induced by glycolipid-containing mycolic acid in mice. Infect Immun. 1993 Jul;61(7):2872–2878. [PMC free article] [PubMed]
  • Baroni CD, De Franceschi GS, Uccini S, Adorini L, Cnen GD, Ruco L. Biological effects of Escherichia coli lipopolysaccharide (LPS) in vivo. I. Selection in the mouse thymus of killer and helper cells. Immunology. 1976 Aug;31(2):217–224. [PubMed]
  • Fehsel K, Kröncke KD, Kolb H, Kolb-Bachofen V. In situ nick-translation detects focal apoptosis in thymuses of glucocorticoid- and lipopolysaccharide-treated mice. J Histochem Cytochem. 1994 May;42(5):613–619. [PubMed]
  • Fehsel K, Kröncke KD, Meyer KL, Huber H, Wahn V, Kolb-Bachofen V. Nitric oxide induces apoptosis in mouse thymocytes. J Immunol. 1995 Sep 15;155(6):2858–2865. [PubMed]
  • Fu Y, Paul RD, Wang Y, Lopez DM. Thymic involution and thymocyte phenotypic alterations induced by murine mammary adenocarcinomas. J Immunol. 1989 Dec 15;143(12):4300–4307. [PubMed]
  • Goren MB, D'Arcy Hart P, Young MR, Armstrong JA. Prevention of phagosome-lysosome fusion in cultured macrophages by sulfatides of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2510–2514. [PubMed]
  • Hernández-Caselles T, Stutman O. Immune functions of tumor necrosis factor. I. Tumor necrosis factor induces apoptosis of mouse thymocytes and can also stimulate or inhibit IL-6-induced proliferation depending on the concentration of mitogenic costimulation. J Immunol. 1993 Oct 15;151(8):3999–4012. [PubMed]
  • Kaneda K, Sumi Y, Kurano F, Kato Y, Yano I. Granuloma formation and hemopoiesis induced by C36-48-mycolic acid-containing glycolipids from Nocardia rubra. Infect Immun. 1986 Dec;54(3):869–875. [PMC free article] [PubMed]
  • Kasahara K, Kobayashi K, Shikama Y, Yoneya I, Kaga S, Hashimoto M, Odagiri T, Soejima K, Ide H, Takahashi T, et al. The role of monokines in granuloma formation in mice: the ability of interleukin 1 and tumor necrosis factor-alpha to induce lung granulomas. Clin Immunol Immunopathol. 1989 Jun;51(3):419–425. [PubMed]
  • Kusumi A, Abo T, Masuda T, Sugiura K, Seki S, Ohteki T, Okuyama R, Kumagai K. Lymphotoxin activates hepatic T cells and simultaneously induces profound thymic atrophy. Immunology. 1992 Oct;77(2):177–184. [PubMed]
  • Lin YS, Lei HY, Low TL, Shen CL, Chou LJ, Jan MS. In vivo induction of apoptosis in immature thymocytes by staphylococcal enterotoxin B. J Immunol. 1992 Aug 15;149(4):1156–1163. [PubMed]
  • Natsuhara Y, Oka S, Kaneda K, Kato Y, Yano I. Parallel antitumor, granuloma-forming and tumor-necrosis-factor-priming activities of mycoloyl glycolipids from Nocardia rubra that differ in carbohydrate moiety: structure-activity relationships. Cancer Immunol Immunother. 1990;31(2):99–106. [PubMed]
  • Norimatsu M, Ono T, Aoki A, Ohishi K, Tamura Y. In-vivo induction of apoptosis in murine lymphocytes by bacterial lipopolysaccharides. J Med Microbiol. 1995 Oct;43(4):251–257. [PubMed]
  • Skalka M, Matyásová J, Cejková M. Dna in chromatin of irradiated lymphoid tissues degrades in vivo into regular fragments. FEBS Lett. 1976 Dec 31;72(2):271–274. [PubMed]
  • Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. [PubMed]
  • Tabata A, Kaneda K, Watanabe H, Abo T, Yano I. Kinetics of organ-associated natural killer cells and intermediate CD3 cells during pulmonary and hepatic granulomatous inflammation induced by mycobacterial cord factor. Microbiol Immunol. 1996;40(9):651–658. [PubMed]
  • Wang SD, Huang KJ, Lin YS, Lei HY. Sepsis-induced apoptosis of the thymocytes in mice. J Immunol. 1994 May 15;152(10):5014–5021. [PubMed]
  • Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. [PubMed]
  • Yamamoto K, Kakinuma M, Kato K, Okuyama H, Azuma I. Relationship of anti-tuberculous protection to lung granuloma produced by intravenous injection of synthetic 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine with or without specific antigens. Immunology. 1980 Aug;40(4):557–564. [PubMed]
  • Yano I, Tomiyasu I, Kitabatake S, Kaneda K. Granuloma forming activity of mycolic acid-containing glycolipids in nocardia and related taxa. Acta Leprol. 1984 Oct-Dec;2(2-4):341–349. [PubMed]
  • Zhang YH, Takahashi K, Jiang GZ, Kawai M, Fukada M, Yokochi T. In vivo induction of apoptosis (programmed cell death) in mouse thymus by administration of lipopolysaccharide. Infect Immun. 1993 Dec;61(12):5044–5048. [PMC free article] [PubMed]

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