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A Temporal Code to generate Specificity in Inflammatory Signaling
Author(s) -
Hoffmann Alexander
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.538.2
Subject(s) - stimulus (psychology) , gene expression , transcription factor , biology , computational biology , neuroscience , gene , immune system , microbiology and biotechnology , computer science , immunology , genetics , psychology , psychotherapist
The immune system responds specifically and appropriately to diverse pathogens. Strikingly, distinct gene expression programs all require the same transcription factor: NF‐kappaB. Interestingly, different stimuli lead to different dynamic profiles of NF‐kappaB activity. In order to investigate the role of dynamic regulation further, we constructed a mathematical model that recapitulates the control of NF‐kappaB activation by the regulated synthesis and degradation of the three canonical IkappaB proteins. Guided by computational simulations, we engineered a mutant cell line that is defective in NF‐kappaB 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. I will 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.