ABSTRACT: BACKGROUND: Biological effects of nuclear factor-kappaB (NFkappaB) can differ tremendously depending on the cellular context. For example, NFkappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NFkappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NFkappaB, involving a lack of inhibitor of kappaB (IkappaBalpha) protein reappearance. Permanent activation of the upstream kinase IKKbeta results from UVB- induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized IkappaBalpha. RESULTS: To investigate the mechanism underlying the general PP2A-mediated tuning of IKKbeta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKKbeta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKKbeta phosphorylation thus allowing for IkappaBalpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKKbeta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of IkappaBalpha reappearance, is not a direct UVB action but requires instrumentality. CONCLUSIONS: The model developed here can be used as a reliable building block of larger NFkappaB models and offers comprehensive simplification potential for future modeling of NFkappaB signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NFkappaB, which is crucial for the development of new anti-cancer strategies.