TNF-α is the critical mediator of the cyclic AMP-induced apoptosis of CD8(+)4(+) double-positive thymocytes Journal Article


Authors: Guevara-Patiño, J. A.; Ivanov, V. N.; Lacy, E.; Elkon, K. B.; Marino, M. W.; Nikolić-Žugić, J.
Article Title: TNF-α is the critical mediator of the cyclic AMP-induced apoptosis of CD8(+)4(+) double-positive thymocytes
Abstract: Apoptosis is one of the key regulatory mechanisms in tissue modeling and development. In the thymus, 95-98% of all thymocytes die by apoptosis because they failed to express a TCR with an optimal affinity for the selecting intrathymic peptide-MHC complexes. We studied the possible role of two prominent nerve growth factor (NGF-TNF) family member systems, Fas ligand (FasL)-Fas receptor (FasR) and TNF-α-TNFR, in apoptosis of murine CD8+4+ double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3ε-mediated apoptosis of DP thymocytes was found not to be dependent on either of the two systems. The FasL-FasR system was also found to be dispensable for the cAMP-mediated apoptosis. By contrast, cAMP agonists (dibutyryl-cAMP and forskolin) induced apoptosis via TNF-α, as evidenced by 1) the ability of anti-TNF-α mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose-dependent manner; and 2) increased resistance of DP thymocytes from TNF-α(-/-) and TNFR I(-/-)II(-/-) animals to cAMP agonist- mediated apoptosis, cAMP agonists induced DP thymocyte death by a combination of two mechanisms: first, they induced selective up-regulation of TNF-α production, and, second, they sensitized DP thymocytes to TNF-α. The latter effect may be due to the down-regulation of TNFR-associated factor 2 protein. These results identify TNF-α as the critical mediator of cAMP-induced apoptosis in thymocytes and provide a molecular explanation for how the cAMP stimulators, including the sex steroids, may modulate T cell production output, as observed under physiological and pharmacological conditions.
Keywords: dose response; nonhuman; cd8 antigen; animal cell; mouse; animals; mice; mice, knockout; cell death; apoptosis; fas antigen; mice, inbred c57bl; lymphocyte activation; tumor necrosis factor alpha; tumor necrosis factor-alpha; thymus; cyclic amp; t-lymphocyte subsets; cd4 antigen; antigens, cd4; thymocyte; antigens, cd8; mice, inbred mrl lpr; receptors, tumor necrosis factor; nerve growth factor; forskolin; dose-response relationship, immunologic; priority journal; article; receptor-cd3 complex, antigen, t-cell; bucladesine
Journal Title: Journal of Immunology
Volume: 164
Issue: 4
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2000-02-15
Start Page: 1689
End Page: 1694
Language: English
PUBMED: 10657611
PROVIDER: scopus
DOI: 10.4049/jimmunol.164.4.1689
DOI/URL:
Notes: Export Date: 18 November 2015 -- Source: Scopus
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MSK Authors
  1. Elizabeth H Lacy
    68 Lacy
  2. Michael W. Marino
    34 Marino