Impaired Induction ofc-fos/c-junGenes and of Transcriptional Regulatory Proteins Binding Distinctc-fos/c-junPromoter Elements in Activated Human T Cells during Aging

• Published in: Cellular immunology 1997-01, Vol.175 (1), p.41-50
• Main Authors: Whisler, Ronald L., Chen, Ming, Beiqing, Liu, Carle, Kristen W.
• Format: Article
• Language: English
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1006/cimm.1996.1048

The activation of transcriptional factor c-Fos/c-Jun AP-1 is essential for normal T cell responsiveness and is often impaired in T cells during aging. In the present study, we investigated whether aberrancies in the regulation ofc-fos/c-junat the mRNA or protein level might underlie the age-associated impairments of AP-1 in human T cells. Whereas T cells from young subjects stimulated with cross-linked anti-CD3ϵ mAb OKT3 plus PMA or with the lectin PHA plus PMA demonstrated considerable increases in c-Fos protein expression, the expression of c-Fos but not c-Jun was markedly reduced in stimulated T cells from certain elderly subjects. In addition, RNase protection assays revealed that anti-CD3/PMA-stimulated T cells from a substantial proportion of elderly subjects exhibited decreased levels ofc-fosand/orc-junmRNA compared to T cells from young subjects. Using electrophoretic mobility shift assays, the levels of nuclear regulatory proteins recognizing the AP-1 consensus TRE motif, the proximalc-junTRE-like promoter element, and thec-fosserum response element (SRE) were determined in resting and stimulated T cells. Although the stimulation of T cells from young subjects resulted in coordinated increases of nuclear protein complexes binding the AP-1 TRE,c-junTRE, andc-fosSRE DNA sequence motifs, age-related reductions in the activation of AP-1 were accompanied by decreased levels ofc-junTRE andc-fosSRE binding complexes. Furthermore, the nuclear protein complexes binding the SRE motif induced in activated T cells of young and elderly subjects contained serum response factor and Elk-1 pointing toward age-related defects in the activation of transcriptional regulatory proteins distinct fromc-jun/AP-1. These results suggest that underlying aberrancies in the induction ofc-fos/c-junas well as their nuclear regulatory proteins may contribute to the age-related impairments of AP-1 activation in human T cells.