NFAT and NFκB activation in T lymphocytes:: A model of differential activation of gene expression

Mathematical models for the regulation of the Ca2+-dependent transcription factors NFAT and NF kappa B that are involved in the activation of the immune and inflammatory responses in T lymphocytes have been developed. These pathways are important targets for drugs, which act as powerful immunosuppressants by suppressing activation of NFAT and NF kappa B in T cells. The models simulate activation and deactivation over physiological concentrations of Ca2+, diacyl glycerol (DAG), and PKC theta using single and periodic step increases. The model suggests the following: (1) the activation NFAT does not occur at low frequencies as NFAT requires calcineurin activated by Ca2+ to remain dephosphorylated and in the nucleus; (2) NF kappa B is activated at lower Ca2+ oscillation frequencies than NFAT as I kappa B is degraded in response to elevations in Ca2+ allowing free NF kappa B to translocate into the nucleus; and (3) the degradation of I kappa B is essential for efficient translocation of NF kappa B to the nucleus. Through sensitivity analysis, the model also suggests that the largest controlling factor for NFAT activation is the dissociation/reassociation rate of the NFAT:calcineurin complex and the translocation rate of the complex into the nucleus and for NF kappa B is the degradation/resynthesis rate of I kappa B and the import rate of I kappa B into the nucleus.