title: TNF-alpha 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-alpha-TNFR, in apoptosis of murine CD8+4+ double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3epsilon-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-alpha, as evidenced by 1) the ability of anti-TNF-alpha mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose-dependent manner; and 2) increased resistance of DP thymocytes from TNF-alpha-/- 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-alpha production, and, second, they sensitized DP thymocytes to TNF-alpha. The latter effect may be due to the down-regulation of TNFR-associated factor 2 protein. These results identify TNF-alpha 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.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Guevara Patiño
authors.forename: V N
authors.initials: VN
authors.lastname: Ivanov
authors.forename: E
authors.initials: E
authors.lastname: Lacy
authors.forename: K B
authors.initials: KB
authors.lastname: Elkon
authors.forename: M W
authors.initials: MW
authors.lastname: Marino
authors.forename: J
authors.initials: J
authors.lastname: Nikolic-Zugić
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003994:Bucladesine / Q000494:pharmacology; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP