236 : Computational model for mechanistic investigation of negative feedback in Interleukin-17 receptor signaling
IL-17 is a proinflammatory cytokine that promotes autoimmunity and protects against certain pathogens. Computational modeling of signaling pathways is a powerful tool to help understand the complexities of these dynamic processes. Here, we present a detailed computational model of signaling downstream of the Interleukin-17 receptor (IL-17R). To manage the complexity of the system we use a rule-based modeling approach, in which signaling proteins are modeled as structured objects and rules describe their biochemical interactions. The model includes 19 molecules and 46 reaction rules, which expand to a reaction network with 168 distinct chemical species – complexes and phosphoforms of the basic molecules – which are connected through a network of 5145 unidirectional reactions. The model is defined and simulated using the BioNetGen software. Dynamical behavior of the network is simulated using ordinary differential equations. This model encompasses major signaling components downstream of IL-17R, including the adaptor molecule Act1 and signaling intermediates TRAF6, TAB, TAK1, and IKK, which are activated through site-specific ubiquitination and phosphorylation. These components work in concert to activate NF- κ B, which in turn promotes the production of pro-inflammatory cytokines and chemokines that are critical for controlling infections by extracellular pathogens. NF- κ B also promotes production of A20, a deubiquitinating enzyme that inhibits NF- κ B activation in multiple settings. We recently showed that A20 acts as a negative regulator of the IL-17 signaling pathway, and here by modeling A20 interactions with TRAF6 and IKK, we are able to recapitulate experimentally-observed oscillations in NF- κ B–dependent A20 expression at both the mRNA and protein levels. Further expansion of the model will enable us to develop and explore novel hypotheses about the role of A20 and other potential regulators of IL-17-mediated signaling.