International Immunology Advance Access originally published online on January 12, 2006
International Immunology 2006 18(2):335-345; doi:10.1093/intimm/dxh372
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Computer simulation of the role of SOCS family protein in helper T cell differentiation
1 Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
2 Division of Immunobiology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Japan
3 Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan
4 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Correspondence to: S. Yamada; E-mail: yamada{at}are.ous.ac.jp
The Th1/Th2 balance determines the nature of an immune response, and particular cytokines, IL-4 and IL-12, determine the direction at the initial stage of activation through TCRs. To investigate how cytokine networks and related signaling pathways impact upon the Th1/Th2 balance, we have developed a computer model for the simulation of Th differentiation. The model includes the IL-4, IL-12 and IFN-
signal transduction pathways, a positive and negative feedback mechanism for cytokine signaling and cytokine-induced negative regulators such as suppressors of cytokine signaling (SOCS)1, SOCS3 and SOCS5. In the present study, we propose a ‘Th0 model’, in which naive T cells differentiate neither into Th1 nor into Th2 states in unskewed cytokine conditions. The model was found to be consistent with experimental results in BALB/c mice. The results of in silico analysis in the condition with SOCS- and signal transducer and activator of transcription (STAT) family-deficient and transgenic states were well fitted to ex vivo experimental results for Th1 and Th2 differentiation profiles in the deficient and transgenic mice. The Th0 model suggested the possibility that dominant Th1 differentiation in STAT4/STAT6 double-deficient mice may be due to a positive feedback effect of initial IFN- production from T cells. The in silico assessment of beneficial effects of inhibitory drugs by simulation analysis with our Th0 model indicated that Janus kinase 3-specific inhibitors might be suitable candidates for the modification of Th2-dominant immune responses. Our results demonstrate that models for the simulation of signaling network, such as our Th0 model, are useful tools for the in silico evaluation of novel drug candidates.
Keywords: computer simulation, cytokine receptors, JAK/STAT pathway, signal transduction, Th1/Th2 cells