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Abstract
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 F/F.
Graphical Abstract
Disclosure statement
The authors declare that they have no competing interests.
Notes on contributors
Shabnam Khatibi is a research fellow at the Monash University, Melbourne. She received her PhD from the University of Melbourne in 2016. She finished her bachelor in Physics from Sharif University of Technology, Tehran, Iran (2011).
Jeff Babon is a laboratory head at WEHI, structural biology division. His focus is on how blood and immune systems are carefully maintained by the action of proteins called cytokines.
John Wagner leads the IBM Research Collaboratory for Life Sciences-Melbourne at the Victorian Life Sciences Computation Initiative at the University of Melbourne. He obtained his BS, MS and PhD in Applied Mathematics from University of California, Davis, where he worked on cellular calcium regulation with Joel Keizer at the Institute of Theoretical Dynamics. John then received an NIH NRSA Postdoctoral Fellowship, working with Les Loew at the National Resource for Cellular Analysis and Modeling at the University of Connecticut Health Center.
Jonathan H. Manton holds a distinguished Chair at the University of Melbourne with the title Future Generation Professor. He is also an Adjunct Professor in the Mathematical Sciences Institute at the Australian National University. He is a Fellow of the Australian Mathematical Society (FAustMS) and a Fellow of the Institute of Electrical and Electronics Engineers (FIEEE).
Chin Wee Tan is a research fellow at WEHI. His focus is on using computational and mathematical techniques to study colon cancer.
Hong-Jian Zhu has an academic appointment in the department of surgery at the University of Melbourne. His focus is mainly on cancer signalling.
Sam Wormald is a research fellow at WEHI. His focus is on systems biology and personalized medicine.
Antony W. Burgess is one of the top cancer researchers and has been Director of the Ludwig Institute for Cancer Research in Melbourne and Professor of Surgery at the Royal Melbourne Hospital, University of Melbourne since 1980. He has an illustrious research history with over 250 publications to his name and has given numerous key-note speeches at Institutes and conferences around the world. Burgess is also a strong force in the advancement of cancer management and research, having been involved in at least thirty scientific committees, boards and funds.