Regulation of transcription factor NF KAPPA B in immune senescence

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Abstract

The Rel/NF kappa B family of eukaryotic transcription factors are critical in immune and inflammatory processes regulating the expression of a wide variety of cytokines including IL-1, IL-2, IL-6, TNF-alpha and GM-CSF. Its ubiquitous distribution, rapid induction and regulation, the complexity of its subunits and its apparent involvement in several diseases has made this transcription factor a subject of intense study in normal cellular growth and cancer. Emerging studies have implicated a role for this transcription factor in the normal processes of aging. As significant declines in immune function is a natural concomitant to advancing age, the regulation of transcription factor NF kappa B appears to play a pivotal role in immune dysregulation during senescence, contributing to down regulation of both IL-2 and IL-2 receptor-alpha expression. Our studies have contributed to understanding the regulation of lowered NF kappa B induction in T cells during aging in humans and mice. Since we have shown that the lowered induction of NF kappa B in activated T cells from the elderly can be attributed to impaired degradation of the inhibitor I kappa B-alpha due to lowered proteasomal activity, we suspect that a similar alteration in proteasomal activity may be operative in age-dependent failure of immune function including the inability to initiate DNA synthesis following activation, skewing of T cell repertoire, lowered cytolytic activity and accumulation of aberrant proteins. Understanding the regulation of the proteasome pathway during immune senescence may provide new avenues for therapeutic intervention for immune based geriatric diseases.

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