Mathematical modelling of interferon-γ signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity

Rateitschak, Katja; Karger, Anna; Fitzner, Brit; Lange, Falko; Jaster, Robert

doi:10.1016/j.cellsig.2009.09.019

Cited by 35 publications

(46 citation statements)

References 35 publications

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“…By these means, permanent monitoring of the cytokine receptor activity and precise adjustment of the transcriptional output are ensured. Such a sensor function of continuous STAT activation and inactivation has been proposed by mathematical modeling (34,35). Coupling of processive transcription with a reduction in promoter occupancy could result from a promoter displacement of STAT1 or from prevention of STAT1 recruitment after the onset of transcription.…”

Section: Resultsmentioning

confidence: 99%

Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

Wiesauer

Gaumannmüller

Steinparzer

et al. 2015

Molecular and Cellular Biology

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Interferons regulate immunity by inducing DNA binding of the transcription factor STAT1 through Y701 phosphorylation. Transcription by STAT1 needs to be restricted to minimize the adverse effects of prolonged immune responses. It remains unclear how STAT1 inactivation is regulated such that the transcription output is adequate. Here we show that efficient STAT1 inactivation in macrophages is coupled with processive transcription. Ongoing transcription feeds back to reduce the promoter occupancy of STAT1 and, consequently, the transcriptional output. Once released from the promoter, STAT1 is ultimately inactivated by Y701 dephosphorylation. We observe similar regulation for STAT2 and STAT3, suggesting a conserved inactivation mechanism among STATs. These findings reveal that STAT1 promoter occupancy in macrophages is regulated such that it decreases only after initiation of the transcription cycle. This feedback control ensures the fidelity of cytokine responses and provides options for pharmacological intervention. Cytokines perform their functions as key regulators of immune responses through activation of the JAK-STAT signaling pathway (1). Inadequate (either low or exacerbated) cytokine signaling may result in diseases such as immunodeficiency, autoimmunity, or cancer (2, 3). The strength of cytokine responses is regulated by various positive and negative feedback mechanisms that act at all steps of the signaling pathway: the cytokine receptors, JAKs, and STAT transcription factors. Yet it remains unclear how the process of cytokine-induced transcription is controlled once the transcription machinery has been turned on by activated STAT.STAT1 is indispensable for the biological function of interferons (IFNs), which are crucial cytokines for antiviral and antibacterial immunity. STAT1 nuclear translocation and DNA binding are activated by JAK-mediated phosphorylation of Y701. Other modifications that tune STAT1 function in IFN signaling include CDK8-mediated S727 phosphorylation, IB kinase ε (IKKε)-mediated S708 phosphorylation, and K703 sumoylation (4-6). Y701-phosphorylated STAT1 binds to target gene promoters in two major forms: (i) STAT1 homodimers induced by type I, II, and III IFNs bind to gamma interferon-activated sequence (GAS) elements, and (ii) the trimeric interferon-stimulated gene factor 3 (ISGF3; composed of STAT1, STAT2, and IRF9) induced by type I and III IFNs binds to interferon-stimulated response elements (ISRE) (1, 7). The principal mechanism of STAT1 inactivation is Y701 dephosphorylation, which causes both STAT1 homodimers and ISGF3 to lose their DNA-binding activity and to relocate to the cytoplasm. The nuclear T-cell protein tyrosine phosphatase (TC-PTP) is the major Y701-directed phosphatase (8). STAT1 acetylation was reported to facilitate dephosphorylation by TC-PTP (9), but this issue has been controversial (10). The access of phosphatase to phosphorylated Y701 appears to be restricted, since DNA-bound STAT1 is protected from Y701 dephosphorylation (11,12). For type II IFN (IFN-␥) ...

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Section: Resultsmentioning

confidence: 99%

Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

Wiesauer

Gaumannmüller

Steinparzer

et al. 2015

Molecular and Cellular Biology

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“…Future work will be performed to identify the relationship between these factors and their contributions to signaling pathways in the granuloma and to add them to our computational model. We employed simplified versions of recently published models for STAT1, STAT3, and NF-B pathways (88,90,94). We use two representative intracellular species for each signaling pathway: a phosphorylated nuclear species (denoted with N) and a response species (denoted with R) (Fig.…”

Section: Models Of Stat1 Stat3 and Nf-b Dynamicsmentioning

confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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“…Specifically, IFNγ inhibited PSC proliferation more efficiently than tumour cell growth. The stronger biological effect of IFNγ in PSC correlated with a more pronounced nuclear accumulation of STAT1 in the stroma cells [4]–[6], raising the question which molecular mechanisms are underlying these observations.…”

Section: Introductionmentioning

confidence: 99%

Parameter Identifiability and Sensitivity Analysis Predict Targets for Enhancement of STAT1 Activity in Pancreatic Cancer and Stellate Cells

et al. 2012

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The present work exemplifies how parameter identifiability analysis can be used to gain insights into differences in experimental systems and how uncertainty in parameter estimates can be handled. The case study, presented here, investigates interferon-gamma (IFNγ) induced STAT1 signalling in two cell types that play a key role in pancreatic cancer development: pancreatic stellate and cancer cells. IFNγ inhibits the growth for both types of cells and may be prototypic of agents that simultaneously hit cancer and stroma cells. We combined time-course experiments with mathematical modelling to focus on the common situation in which variations between profiles of experimental time series, from different cell types, are observed. To understand how biochemical reactions are causing the observed variations, we performed a parameter identifiability analysis. We successfully identified reactions that differ in pancreatic stellate cells and cancer cells, by comparing confidence intervals of parameter value estimates and the variability of model trajectories. Our analysis shows that useful information can also be obtained from nonidentifiable parameters. For the prediction of potential therapeutic targets we studied the consequences of uncertainty in the values of identifiable and nonidentifiable parameters. Interestingly, the sensitivity of model variables is robust against parameter variations and against differences between IFNγ induced STAT1 signalling in pancreatic stellate and cancer cells. This provides the basis for a prediction of therapeutic targets that are valid for both cell types.

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Mathematical modelling of interferon-γ signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity

Cited by 35 publications

References 35 publications

Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Parameter Identifiability and Sensitivity Analysis Predict Targets for Enhancement of STAT1 Activity in Pancreatic Cancer and Stellate Cells

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