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Title:	Transient oscillatory dynamics of interferon beta signaling in macrophages
Author:	Pertsovskaya, Inna; Abad Adan, Elena; Domedel Puig, Núria; García Ojalvo, Jordi; Villoslada, Pablo
Abstract:	Background: Interferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway. IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis. The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions. Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays. The experimental results were interpreted by means of a theoretical model of the pathway. Results: Phosphorylation of the STAT1 protein (pSTAT1) and mRNA levels of the pSTAT1 inhibitor SOCS1 displayed an attenuated oscillatory behavior after IFN-beta activation. In turn, mRNA levels of the interferon regulatory factor IRF1 grew rapidly in the first 50–90 minutes after stimulation until a maximum value, and started to decrease slowly around 200–250 min. The analysis of our kinetic model identified a significant role of the negative feedback from SOCS1 in driving the observed damped oscillatory dynamics, and of the positive feedback from IRF1 in increasing STAT1 basal levels. Our study shows that the system works as a biological damped relaxation oscillator based on a phosphorylation-dephosphorylation network centered on STAT1. Moreover, a bifurcation analysis identified translocation of pSTAT1 dimers to the nucleus as a critical step for regulating the dynamics of type I IFN pathway in the first steps, which may be important in defining the response to IFN-beta therapy. Conclusions: The immunomodulatory effect of IFN-beta signaling in macrophages takes the form of transient oscillatory dynamics of the JAK-STAT pathway, whose specific relaxation properties determine the lifetime of the cellular response to the cytokine.
Abstract:	This work was supported by the EU 6FP ComplexDis project (NEST-043241), the EU 7FP – Marie Curie initial training network UEPHA*MS (ITN-212877) and Fundacion Cellex to PV; by the Spanish network of excellence in MS of the Instituto de Salud Carlos III, Spain to PV and JGO (RD07/0060) and by the Fundación Mutua Madrileña to PV and JGO; by a grant of the Ministerio de Economia y Competitividad and Fondo Europeo de Desarrollo Regional (Spain, project FIS2012-37655) and by the ICREA Academia program to JGO
Subject(s):	-Resposta immunitària -Esclerosi múltiple -Type I interferon pathway -Interferon-beta -Ordinary differential equation -Oscillations -Multiple sclerosis -Immunotherapy
Rights:	© 2013 Pertsovskaya et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/2.0
Document type:	Article Article - Published version
Published by:	BioMed Central
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