title: Down-regulation of CD28 expression by TNF-alpha.
abstract: Aging and chronic inflammatory syndromes, such as rheumatoid arthritis, are associated with high frequencies of CD4(+)CD28(null) T cells, which are rarely seen in healthy individuals younger than 40 years. Inasmuch as rheumatoid arthritis and aging are also associated with elevated levels of TNF-alpha, we examined whether this proinflammatory cytokine influences CD28 expression. Incubation of T cell lines and clones as well as Jurkat cells with TNF-alpha induced a reduction in the levels of cell surface expression of CD28. This effect of TNF-alpha was reversible; however, continuous culture of CD4(+)CD28(+) T cell clones in TNF-alpha resulted in the appearance of a CD28(null) subset. In reporter gene bioassays, TNF-alpha was found to inhibit the activity of the CD28 minimal promoter. Inactivation of the promoter was accompanied by a marked reduction in DNA-protein complex formation by two DNA sequence motifs corresponding to the transcriptional initiator of the CD28 gene. Indeed, in vitro transcription assays showed that nuclear extracts from TNF-alpha-treated cells failed to activate transcription of DNA templates under the control of a consensus TATA box and the CD28 initiator sequences. In contrast, similar extracts from unstimulated T cells supported transcription. These results demonstrate that TNF-alpha directly influences CD28 gene transcription. We propose that the emergence of CD4(+)CD28(null) T cells in vivo is facilitated by increased production of TNF-alpha.
authors.affiliation: Department of Medicine and Immunology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bryl
authors.forename: A N
authors.initials: AN
authors.lastname: Vallejo
authors.forename: C M
authors.initials: CM
authors.lastname: Weyand
authors.forename: J J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000375:Aging / Q000378:metabolism; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D018106:CD28 Antigens / Q000096:biosynthesis* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects; D002474:Cell-Free System; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016385:TATA Box; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D017304:Annexin A5; D018106:CD28 Antigens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D002166:Camptothecin