Coulibaly2019 - Interleukin-15 Signaling in HIF-1a Regulation in Natural Killer Cells

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Short description
This is a mathematical model comprised of non-linear ordinary differential equations describing the dynamic relationship between hypoxia-inducible factor-1 alpha (HIF-1a) mRNA, HIF-1a protein, and interleukin-15-mediated upstream signalling events in natural killer cells from human blood. Regulatory expressions are also included for mammalian target of rapamycin (mTOR), nuclear factor-kappa beta, and signal transducer and activator of transcription 3 (STAT3).
Related Publication
  • Interleukin-15 Signaling in HIF-1α Regulation in Natural Killer Cells, Insights Through Mathematical Models.
  • Coulibaly A, Bettendorf A, Kostina E, Figueiredo AS, Velásquez SY, Bock HG, Thiel M, Lindner HA, Barbarossa MV
  • Frontiers in Immunology , 1/ 2019 , Volume 10 , pages: 2401 , PubMed ID: 31681292
  • Department of Anesthesiology and Surgical Intensive Care Medicine, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
  • Natural killer (NK) cells belong to the first line of host defense against infection and cancer. Cytokines, including interleukin-15 (IL-15), critically regulate NK cell activity, resulting in recognition and direct killing of transformed and infected target cells. NK cells have to adapt and respond in inflamed and often hypoxic areas. Cellular stabilization and accumulation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) is a key mechanism of the cellular hypoxia response. At the same time, HIF-1α plays a critical role in both innate and adaptive immunity. While the HIF-1α hydroxylation and degradation pathway has been recently described with the help of mathematical methods, less is known concerning the mechanistic mathematical description of processes regulating the levels of HIF-1α mRNA and protein. In this work we combine mathematical modeling with experimental laboratory analysis and examine the dynamic relationship between HIF-1α mRNA, HIF-1α protein, and IL-15-mediated upstream signaling events in NK cells from human blood. We propose a system of non-linear ordinary differential equations with positive and negative feedback loops for describing the complex interplay of HIF-1α regulators. The experimental design is optimized with the help of mathematical methods, and numerical optimization techniques yield reliable parameter estimates. The mathematical model allows for the investigation and prediction of HIF-1α stabilization under different inflammatory conditions and provides a better understanding of mechanisms mediating cellular enrichment of HIF-1α. Thanks to the combination of in vitro experimental data and in silico predictions we identified the mammalian target of rapamycin (mTOR), the nuclear factor-κB (NF-κB), and the signal transducer and activator of transcription 3 (STAT3) as central regulators of HIF-1α accumulation. We hypothesize that the regulatory pathway proposed here for NK cells can be extended to other types of immune cells. Understanding the molecular mechanisms involved in the dynamic regulation of the HIF-1α pathway in immune cells is of central importance to the immune cell function and could be a promising strategy in the design of treatments for human inflammatory diseases and cancer.
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer

Metadata information

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasProperty (4 statements)
Mathematical Modelling Ontology Ordinary differential equation model
NCIt Natural Killer Cell
NCIt Interleukin-15

Curation status


Connected external resources

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Model files

Coulibaly2019.xml SBML L2V4 Representation of Coulibaly2019 - Interleukin-15 Signaling in HIF-1a Regulation in Natural Killer Cells 110.16 KB Preview | Download

Additional files

Coulibaly2019.cps COPASI file of Coulibaly2019 - Interleukin-15 Signaling in HIF-1a Regulation in Natural Killer Cells 177.66 KB Preview | Download
Coulibaly2019.sedml SED-ML file of Coulibaly2019 - Interleukin-15 Signaling in HIF-1a Regulation in Natural Killer Cells 6.79 KB Preview | Download

  • Model originally submitted by : Johannes Meyer
  • Submitted: Nov 18, 2019 3:30:25 PM
  • Last Modified: Nov 18, 2019 3:30:25 PM
  • Version: 2 public model Download this version
    • Submitted on: Nov 18, 2019 3:30:25 PM
    • Submitted by: Johannes Meyer
    • With comment: Automatically added model identifier BIOMD0000000867
: Variable used inside SBML models

Species Initial Concentration/Amount
y7 NF KB

1.0 nmol
y5 HIF 1b

1.0 nmol
y6 HIF 1 Complex

C28553 ; C20214 ; Complex
0.05 nmol
y10 HIF 1a aOH

C20214 ; MOD:00677
0.9 nmol
y3 mTOR

1.0 nmol
y2 Akt

1.0 nmol
Reactions Rate Parameters
y7_NF_KB => compartment*d7*y7_NF_KB d7 = 0.914
y6_HIF_1_Complex => y4_HIF_1a + y5_HIF_1b compartment*k5*y6_HIF_1_Complex k5 = 75.895
y5_HIF_1b => compartment*d5*y5_HIF_1b d5 = 0.196
y4_HIF_1a + y5_HIF_1b => y6_HIF_1_Complex compartment*k4*y4_HIF_1a*y5_HIF_1b k4 = 76.196
y10_HIF_1a_aOH => compartment*d10*y10_HIF_1a_aOH d10 = 0.935
y3_mTOR => compartment*d3*y3_mTOR d3 = 0.919
=> y7_NF_KB compartment*a7 a7 = 0.0
=> y7_NF_KB; y6_HIF_1_Complex compartment*k14*y6_HIF_1_Complex k14 = 16.528
=> y2_Akt compartment*a2 a2 = 0.848
Curator's comment:
(added: 18 Nov 2019, 15:30:11, updated: 18 Nov 2019, 15:30:11)
Reproduced plots of Figure 6 in the original publication. Model simulated and plots produced using COPASI 4.24 (Build 197).