title: Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT.
abstract: Although transcriptional factors AP-1 and nuclear factor of activated T cells (NF-AT) are important for the normal induction of IL-2, it is unknown if the age-related decline in IL-2 production by activated human T cells may be associated with aberrancies in transcriptional regulatory proteins. In the current studies, IL-2 production by T cells from elderly (mean 78 years) and young (mean 37 years) humans was measured in cultures stimulated with PHA, PHA plus PMA, crosslinked anti-CD3 mAB OKT3 plus PMA, or PMA plus ionomycin. Substantial decreases of IL-2 production were observed for cell cultures from 7 of 12 elderly individuals in response to the different stimuli, whereas the levels of IL-2 produced by stimulated T cells from other elderly individuals were equivalent to those observed for stimulated T cells of young subjects. Analyses of nuclear extracts by electrophoretic DNA mobility shift assays showed that decreased IL-2 production by stimulated T cells of elderly individuals was closely associated with impairments in the activation of both AP-1 and NF-AT. By contrast, T cells from elderly subjects with normal levels of IL-2 production exhibited normal activation of AP-1 and NF-AT. In addition, the results of competition experiments analyzing the normal components of NF-AT showed that the age-related reductions in stimulus-dependent NF-AT complexes corresponded to the slow migrating complexes that were composed of c-Fos/c-Jun AP-1. The resting and stimulated levels of NF kappa B were reduced in T cells from certain elderly individuals; however, alterations of NF kappa B did not correlate with changes in IL-2 expression. Thus, these results show that age-related impairments in the activation of AP-1 and NF-AT are closely associated with decreased expression of IL-2 and further suggest that aberrancies in the signaling pathways important for the induction of transcriptionally active c-Fos/c-Jun AP-1 may contribute to the impaired activation of NF-AT.
authors.affiliation: Department of Medical Biochemistry, William H. Davis Medical Research Center, Ohio State University, Columbus 43210-1228, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Whisler
authors.forename: L
authors.initials: L
authors.lastname: Beiqing
authors.forename: M
authors.initials: M
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors