NF-κB responds to absolute differences in cytokine concentrations
| Autor: | Marie Oliver Metzig, Parthiv Patel, Hsiung-Lin Tu, Andrew Wang, Savaş Tay, Kabir Husain, Alexander Hoffmann, Arvind Murugan, Jing Lin, Minjun Son |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Gene regulatory network Biochemistry Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system NF-KappaB Inhibitor alpha medicine Receptor Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences Chemistry Kinase Tumor Necrosis Factor-alpha NF-kappa B NF-κB Cell Biology Cell biology IκBα Cytokine Gene Expression Regulation Cytokines 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Science Signaling, vol 14, iss 666 Sci Signal |
| Popis: | Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure such dynamic inputs is not well understood. Here, we used microfluidic single-cell analysis and mathematical modeling to study how the NF-κB pathway responds to immune inputs that vary over time such as increasing, decreasing, or fluctuating cytokine signals. We found that NF-κB activity responded to the absolute difference in cytokine concentration and not to the concentration itself. Our analyses revealed that negative feedback by the regulatory proteins A20 and IκBα enabled differential responses to changes in cytokine dose by providing a short-term memory of previous cytokine concentrations and by continuously resetting kinase cycling and receptor abundance. Investigation of NF-κB target gene expression showed that cells exhibited distinct transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments. |
| Databáze: | OpenAIRE |
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