Introduction Interleukin-1 (IL-1) and its signalling receptor (IL-1RI) are well known as central regulators of vascular repair and injury. Specifically, activation of the NF-kB pathway and its control of inflammatory and anti-apoptotic signals have pronounced effects on development of atherosclerosis. TILRR is a recently identified co-receptor to IL-1RI, which amplifies NF-kB activities and alters gene activation profiles induced by IL-1.1 TILRR is highly expressed at sites of vascular inflammation where its recruitment to the IL-1 receptor complex enhances inflammatory signals, reduces apoptosis and triggers cytoskeletal collapse during IL-1 stimulation. Mutants of TILRR (R425 and D448) have been produced, and demonstrated to selectively reduce enhanced inflammatory or anti-apoptotic signals through the IL-1 receptor complex.2
Methods and Results We have developed an agent-based model of the IL-1R signalling pathway capable of qualitatively reproducing in vitro data of IkBa degradation and NF-kB nuclear translocation. The model describes accurately the impact of varying TILRR expression, the effects of varying the affinity for adaptor proteins at the level of the receptor complex, and the specific regulation of NF-kB controlled responses induced by wild type TILRR and the R425 and D448 mutants. Further investigation with this model identifies a novel regulation of the IL-1 signalling response through the binding and release of IkBa by the cytoskeleton, which has previously been shown to sequester 2/3 of cellular IkBa.3 Here we demonstrate the relevance of the cytoskeletal pool of IkBa in NF-kB control using the computational model in combination with in vitro experiments.
Conclusions Using agent-based modelling we predict that both cytoskeletal sequestering of IkBa and its release upon IL-1 stimulation impact the kinetics and levels of the cellular response. The effects are expected to play a significant part in the altered gene activation profiles induced by IL-1RI activation at sites of inflammation during development of atherosclerosis.
Acknowledgements The research is supported by BBSRC grant BB/J009687/1 to EEQ and MWH.
Zhang X, Shephard F, Kim HB, Palmer IR, McHarg S, Fowler GJ, O’Neill LA, Kiss-Toth E, and Qwarnstrom EE. TILRR, a novel IL-1RI co-receptor, potentiates MYD88-recruitment to control ras-dependent amplification of NF-kappB. J Biol Chem 2010;285(10):7222–7232
Zhang X, Montago-Pino G, Shephard F, Kiss-Toth E, and Qwarnstrom EE. Distinct control of MyD88 adapter-dependent and Akt kinase regulated responses by the IL-1RI co-receptor TILRR . J Biol Chem2012 ;287:12348–12352; doi:10.1074/jbc.C111.321711
Pogson M, Holcombe M, Smallwood R, Yang L, and Qwarnstrom EE. Introducing spatial information into predictive NF-kB modelling- an agent based approach. PLoS ONE 2008;3(6):e2367
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