284185 Resolution of Incoherent Immune Stimuli Through Intracellular Crosstalk

Wednesday, October 31, 2012: 1:50 PM
Crawford East (Westin )
Camila Benaim, Computer Science, ISP, Northwestern University, Evanston, IL, Yishan Chuang, Chemical and Biologial Engineering, Northwestern University, Evanston, IL and Joshua N. Leonard, Chemical and Biological Engineering, Chemistry of Life Processes Institute, R.H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL

Macrophages play a critical role in maintaining the balance between homeostasis and protective inflammation by adopting either immunostimulatory (M1) or immunosuppressive (M2) phenotypes. Tumors and pathogens manipulate this balance by inducing the production of immunosuppressive stimuli in immune microenvironment, which shifts macrophages into a tumor or pathogen-promoting M2 phenotype. In other experimental work, we discovered that sustained exposure of macrophages to the canonical pro-M2 stimulus IL-10 promotes maintenance of the M2 phenotype even in the presence of IL-12, a stimulus that previously reported to convert tumor-associated M2 cells to a M1 phenotype. This observation contradicts a dominant conceptual model in the field that had motivated clinical administration of IL-12 to cancer patients to overcome local immune dysfunction. In order to investigate potential mechanisms that could mediate this new phenomenon, we developed mechanistic computational models of the IL-10 and IL-12 signaling pathways and key downstream gene circuits involved in cross-regulation. Briefly, IL-10 induces signaling via the transcription factor STAT3, which promotes the production of immunosuppressive mediators as well as suppressors of cytokine signaling 1 and 3 (SOCS1, SOCS3). SOCS1 inhibits signaling downstream of both IL-10 and IL-12, but SOCS3 inhibits signaling downstream from IL-12 but not IL-10. On the other hand, IL-12 signals through STAT4, which promotes the production of immunostimulatory mediators and SOCS1. Therefore, SOCS1 and SOCS3 potentially mediate asymmetric macrophage fate determination through crosstalk between pathways and gene circuits induced by IL-10 and IL-12. A challenge in evaluating such a theory is determining whether multiple observations (qualitative, semi-quantitative, and quantitative) may be integrated into a single parsimonious description of this system that is consistent with all observations. To meet this need, here we describe the use of both stochastic and deterministic simulations to interrogate the properties of this important intracellular circuit and to evaluate potential mechanisms by which this key facet of immune dysfunction in chronic disease may be regulated and therapeutically manipulated.

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