A mathematical model of homeostatic and stimulus-induced regulation of cell death by the transcription factor NF-kappaB in response to TNF

Paul Loriaux, University of California, San Diego

Photo of Paul Loriaux

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine released in response to trauma or infection. Binding of TNF to its cognate receptor (TNFR) results in direct activation of caspase-8 and the apoptotic machinery via the intracellular death domain of TNFR. Healthy cells, however, are highly resistant to TNF-induced apoptosis owing to concurrent activation of nuclear factor kappa B (NF-kB), a pro-inflammatory, anti-apoptotic transcription factor. Recent studies suggest that the anti-apoptotic function of NF-kB may be mediated through cFLIP, whose pseudo-caspase domain prevents activation of caspase-8 by ligand-bound TNFR.

Several mechanisms by which NF-kB regulates cFLIP have been proposed. Expression of cFLIP is known to be induced by NF-kB. Additional regulation of cFLIP levels may be achieved by controlling the activity of JNK kinase. JNK has recently been shown to induce the degradation of cFLIP by activating the E3 ubiquitin ligase, Itch. The anti-apoptotic protein A20, also induced by NF-kB, functions upstream of JNK by inhibiting activation of the MAP3K responsible for activating JNK. Similarly, accumulation of oxygen radicals promotes JNK activity by inhibiting the inactivating MAPK phosphatase. Anti-ROS molecules FHC and Mn-SOD are induced by active NF-kB and have also been implicated in the regulation of JNK.

To investigate the relative importance of these mechanisms under different physiological conditions, we have constructed a mathematical model of TNF-induced NF-kB activation and regulation of the JNK pro-apoptotic pathway. To investigate explicit homeostatic states and their effect on the induced response to TNF stimulation, we have formulated a methodology for deriving closed-form expressions of non-equilibrium steady-state. Extensive model simulation over a range of physiological steady states in conjunction with experimental data from our lab suggests an intriguing hypothesis: that homeostatic versus induced regulation of the pro-apoptotic JNK signal by NF-kB predetermines the cellular response to TNF stimulation.

Abstract Author(s): Paul Loriaux, Rebecca Delker, Shannon Werner, Alexander Hoffmann