Decoding patterns of macrophage TNF production to model NF-κB dynamics and cell-cell communication

Abstract

Abstract Immune and stromal cells communicate through cytokines to initiate intracellular signaling, gene expression, and a multifaceted immune response. Cytokine signaling coordinates the dynamics of intracellular pathways that regulate inflammation. Immune and stromal cells both produce and respond to tumor necrosis factor-alpha (TNF), mediating inflammation and enabling communication between these compartments. The inflammatory role of TNF, activating the nuclear factor-κB (NF-κB) signaling and mitogen-activated protein kinase (MAPK) pathways, is well known. However, the effect of varying the time and amplitude patterns of TNF production in neighboring immune and stromal cells has not been systematically studied. Moreover, little is known about how time and amplitude patterns of an inflammatory signal input impact the nature of inflammatory responses. To study this relationship between production and response to TNF and its role in the dynamics of TNF-dependent NF-κB and MAPK signaling, we are using a systems immunology approach. Specifically, we are experimentally determining the patterns of TNF produced by human macrophages stimulated with heat-killed bacteria and characterizing the effect of these TNF stimulation patterns in the dynamics of NF-κB and MAPK responses in human cell lines. Additionally, we will use these experimental results to calibrate our deterministic 2 feedback with competitor (D2FC) mathematical model and model the dynamics of NF-κB signaling. Findings from this research will likely apply to other cytokine and signaling pathways, contributing to understanding the integration of time varying cytokine stimuli.