TGF-β and IL-6 family signalling crosstalk: an integrated model.

Mathematical models for TGF-β and IL-6 signalling have been linked, providing a platform for analyzing the crosstalk between the systems. An integrated IL-6:TGF-β model was developed via a reduced set of reaction equations which incorporate both feedback loops and appropriate time-delays for transcription and translation processes. The model simulates stable, robust and realistic responses to both ligands. Pulsatile (multiple pulses) inputs for both TGF-β and IL-6 have been simulated to investigate the effects of each ligand on the sensitivity, equilibrium and dynamic responses of the integrated signalling system. In our simulations the crosstalk between constant IL-6 and TGF-β signalling via SMAD7 does not appear to be sufficient to render the cells resistant to TGF-β inhibition. However, the simulations predict that pulsatile IL-6 stimulation would increase SMAD7 levels substantially and consequentially, lead to resistance to TGF-β. The model also allows the prediction of the integrated signalling pathway responses to the mutation of key components, e.g. Gp130