Investigating a temporal code of inflammatory signaling

Alexander Hoffman, UC San Diego

Abstract

Experimental studies have revealed that the inflammatory transcription factor NF-κB is dynamically regulated. Indeed, the immune system responds specifically and appropriately to diverse pathogens. Ex vivo, we show that different inflammatory stimuli also elicit strikingly distinct gene expression programs, but they all require the transcription factor NF-κB. Interestingly, different stimuli lead to different dynamic profiles of NF-κB activity. In order to investigate the role of dynamic regulation further, we constructed a mathematical model that recapitulates the control of NF-κB activation by the regulated synthesis and degradation of the three canonical IκB proteins. Guided by computational simulations, we engineered a mutant cell line that is defective in NF-κB temporally controlled amplitude modulation (AM); these cells are still responsive to inflammatory stimuli but, remarkably, lose stimulus-specificity in gene expression. We therefore postulate the existence of a temporal code to generate stimulus-specific inflammatory gene expression programs. We present computational tools to probe this stimulus-specific temporal code. By perturbing the parameter space pharmacologically, we provide experimental support for computational predictions. Our studies suggest that the temporal code of inflammatory signaling can be harnessed to maximize the specific efficacy of pharmacological agents.

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