Multivariate statistical analysis applied to an IL6 signal transduction model in hepatocytes

Abstract

SUMMARYThis paper introduces the application of linear multivariate statistical techniques, including partial least squares (PLS), canonical correlation analysis (CCA) and reduced rank regression (RRR), into the area of Systems Biology. This new approach aims to extract the important proteins embedded in complex signal transduction pathway models.The analysis is performed on a model of intracellular signalling along the janus-associated kinases/signal transducers and transcription factors (JAK/STAT) and mitogen activated protein kinases (MAPK) signal transduction pathways in interleukin-6 (IL6) stimulated hepatocytes, which produce signal transducer and activator of transcription factor 3 (STAT3).A region of redundancy within the MAPK pathway that does not affect the STAT3 transcription was identified using CCA. This is the core finding of this analysis and cannot be obtained by inspecting the model by eye. In addition, RRR was found to isolate terms that do not significantly contribute to changes in protein concentrations, while the application of PLS does not provide such a detailed picture by virtue of its construction.This analysis has a similar objective to conventional model reduction techniques with the advantage of maintaining the meaning of the states prior to and after the reduction process. A significant model reduction is performed, with a marginal loss in accuracy, offering a more concise model while maintaining the main influencing factors on the STAT3 transcription.The findings offer a deeper understanding of the reaction terms involved, confirm the relevance of several proteins to the production of Acute Phase Proteins and complement existing findings regarding cross-talk between the two signalling pathways.

STAT3 Does Not Regulate Acute Liver Injury After Ischemia/Reperfusion

“…This suggests that the protective effects of IL-6 may be mediated by a different signaling pathway. IL-6 is known to activate other signaling pathways in hepatocytes that are independent of STAT3, including mitogen activated protein kinases, protein kinase C, and peroxisome proliferator activated receptor-δ (14, 15). Interrogation of the roles of these pathways in acute I/R injury is warranted.…”

Systems biology of IL-6, IL-12 family cytokines

“…The original model by Singh and colleagues [42] was applied as a basis for the introduction of methods to simplify signal transduction models [47]. McArdle and coworkers show how a complex original model is translated into a form that is represented by linear predictor/response interrelationships.…”

“…The results indicate that the MAPK pathway does not directly induce nuclear STAT3 transcription factor dimers. Nevertheless, the MAPK pathway plays a role in STAT3 regulation through crosstalk with the Jak/STAT pathway [47], probably due to serine 727 phosphorylation of STAT3.…”