Abstract
Nuclear factor of activated T cells 5 (NFAT5) is the most recently described member of the Rel family of transcription factors, including NF-κB and NFAT1-4, which play central roles in inducible gene expression during the immune response. NFAT5 was initially described to drive osmoprotective gene expression in renal medullary cells, which are routinely faced by high extracellular osmolalities. Recent data however indicate profound biological importance of the mammalian osmotic stress response in view of NFAT5 dependent gene regulation in non-renal tissues. In mononuclear cells and epithelial cells, NFAT5 stimulates the expression of various pro-inflammatory cytokines during elevated ambient tonicity. Accordingly, compared to plasma, the interstitial tonicity of lymphoid organs like spleen and thymus and that of liver is substantially hypertonic under physiological conditions. In addition, anisotonic disorders (hypernatremia, diabetes mellitus, dehydration) entail systemic hyperosmolality, and, in inflammatory disorders, the skin, intestine, and cornea are sites of local hyperosmolality. This article summarizes the current knowledge regarding systemic and local osmotic stress in anisotonic and inflammatory disorders in view of NFAT5 activation and regulation, and NFAT5 dependent cytokine production.
Highlights
Nuclear factor of activated T cells 5 (NFAT5) is the most recently identified member of the Rel family of transcription factors including NF-B and nuclear factors of activated T cells (NFAT) 1-4 [1, 2]
Whereas NFAT1-4 are only found in vertebrates, an ortholog of NFAT5 has been discovered in Drosophila, suggesting that the role of NFAT5 is not restricted to osmoregulatory processes in the kidney medulla in vertebrates, but is relevant to responses present in both vertebrates and invertebrates [7,8,9]
Diverse other conditions are characterized by local osmotic stress, which correlates with the secretion of proinflammatory cytokines by the respective cell type, a direct functional role of NFAT5 has not been demonstrated yet (See Table 2)
Summary
NFAT5 is the most recently identified member of the Rel family of transcription factors including NF-B and nuclear factors of activated T cells (NFAT) 1-4 [1, 2]. The following sections summarize the current knowledge regarding local osmotic stress in human disorders and the role of NFAT5 activation in view of inflammatory cytokine expression under these conditions. 586 Current Genomics, 2010, Vol 11, No 8 stimulates NFAT5 transcriptional activity in response to hypertonicity in renal medullary cells [38, 39].
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