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

摘要

Mathematical models for TGF-beta and IL-6 signalling have been linked, providing a platform for analyzing the crosstalk between the systems. An integrated IL-6:TGF-beta 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-beta 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-beta signalling via SMAD7 does not appear to be sufficient to render the cells resistant to TGF-beta inhibition. However, the simulations predict that pulsatile IL-6 stimulation would increase SMAD7 levels substantially and consequentially, lead to resistance to TGF-beta. The model also allows the prediction of the integrated signalling pathway responses to the mutation of key components, e.g. Gp130 (F/F).