Abstract
Macrophage produced inducible nitric oxide synthase (iNOS) is known to play a critical role in the proinflammatory response against intracellular pathogens by promoting the generation of bactericidal reactive nitrogen species. Robust and timely production of nitric oxide (NO) by iNOS and analogous production of reactive oxygen species are critical components of an effective immune response. In addition to pathogen associated lipopolysaccharides (LPS), iNOS gene expression is dependent on numerous proinflammatory cytokines in the cellular microenvironment of the macrophage, two of which include interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). To understand the synergistic effect of IFN-γ and TNF-α activation, and LPS stimulation on iNOS expression dynamics and NO production, we developed a systems biology based mathematical model. Using our model, we investigated the impact of pre-infection cytokine exposure, or priming, on the system. We explored the essentiality of IFN-γ priming to the robustness of initial proinflammatory response with respect to the ability of macrophages to produce reactive species needed for pathogen clearance. Results from our theoretical studies indicated that IFN-γ and subsequent activation of IRF1 are essential in consequential production of iNOS upon LPS stimulation. We showed that IFN-γ priming at low concentrations greatly increases the effector response of macrophages against intracellular pathogens. Ultimately the model demonstrated that although TNF-α contributed towards a more rapid response time, measured as time to reach maximum iNOS production, IFN-γ stimulation was significantly more significant in terms of the maximum expression of iNOS and the concentration of NO produced.
Highlights
The inducible nitric oxide synthase enzyme plays a critical role in the primary proinflammatory response in macrophages upon pathogen infection
Activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway leads to the formation of phosphorylated STAT1 dimers and activation of the interferon regulatory factor-1 (IRF1), two other key transcription factors used in the regulation of inducible nitric oxide synthase (iNOS) gene production [17]
To modularize the modeling of the network, the signaling pathway was divided into four sections: (1) IFN-γ activated JAK/STAT signal transduction leading to STAT1 dimer formation, (2) LPS activated mitogen-activated protein kinase (MAPK) signal transduction and subsequent NF-κB activation and nuclear translocation, (3) activator protein-1 (AP1), IRF-1, TNF-α, and iNOS gene expression, and (4) metabolic production of nitric oxide and arginine, which is modulated by the NOS enzyme
Summary
The inducible nitric oxide synthase (iNOS) enzyme plays a critical role in the primary proinflammatory response in macrophages upon pathogen infection. Few studies have successfully quantified the mechanistic contribution of cytokine synergism to the temporal dynamics of immune effector response. Given the centrality of effector molecules like nitric oxide in the containment and eventual clearance of pathogenic infections, successfully correlating the host cytokine environment to immunological response can aid in the development of targeted immunomodulatory therapies to combat infection. We developed an integrated computational model of the macrophage proinflammatory response to infection and consequential activation of iNOS gene expression. We investigated the contribution of the local cytokine environment to the actuation of the effector response by exploring the synergy between tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) and the consequences of this synergy on the dynamics of iNOS production
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