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PKR DEPENDENT UPREGULATION OF IMMEDIATE EARLY GENES AND ANTI-INFLAMMATORY CYTOKINE IL-10

Chakrabarti, Arindam
http://rave.ohiolink.edu/etdc/view?acc_num=kent1176136341

Abstract Details

2007, PHD, Kent State University, College of Biomedical Sciences.
Viral infection induces expression and activation of several genes involved directly or indirectly in antiviral defense. Protein kinase R (PKR), a Ser/Thr kinase induced by interferons and activated by double-stranded RNA (dsRNA) is a crucial component in mediating cellular antiviral action. Following activation by dsRNA, PKR initiates antiviral defense by inhibiting translation and inducing apoptosis. Apart from its role in translational inhibition, PKR has been implicated as a key integrator of many other signaling pathways stimulated by lipopolysaccharide, cytokines, growth factors and different types of cellular stresses. In order to define PKR dependent genes to better elucidate its physiological function, gene expression profiling following dsRNA treatment was performed on wild-type (wt) and PKR knockout (pkr-ko) spleen derived macrophage cell lines (SM) cells). The microarray results identified several novel PKR-dependent genes whose expression is induced by dsRNA treatment of mouse macrophages. The expression of early growth response-1 (Egr-1), an immediate early gene was highly induced in a PKR dependent manner on dsRNA treatment. NF-kB was determined to be a key component in regulation of the dsRNA mediated PKR-dependent, Egr-1 induction.Earlier reports have implied a role for PKR in induction and activation of AP-1 family members including c-Fos and ATF2 in response to different stimuli. A novel role for PKR in up-regulation of the AP-1 transcription factor c-Jun in response to dsRNA is documented in this thesis. Depending on the cell type, dsRNA mediated c-Jun induction is shown to be dependent on c-Jun NH2-terminal kinase JNK or extracellular signal related kinase ERK. Additionally, a role for c-AMP response element binding protein CREB is implicated in dsRNA mediated c-Jun induction. Importantly, activation of CREB, in response to dsRNA was impaired in the absence of PKR in SM cells.A role for PKR in the regulation of different pro-inflammatory cytokines has been established from earlier reports. However a role for PKR in regulation of anti-inflammatory cytokine production is not well documented. This study shows for the first time PKR dependent induction of of IL-10 in response to dsRNA. This dissertation demonstrates that the PKR mediated IL-10 induction in response to dsRNA is dependent on JNK and NF-kB. In addition, by bioinformatic and chromatin immunoprecipitation assay, a novel functional NF-kB binding site was identified at the -861/-851 region of the mouse IL-10 promoter. These results suggest that PKR plays a significant role in innate immunity by maintaining a equilibrium between pro- and anti-inflammatory cytokines in response to viral infection.Overall this study provided us with a better understanding of the global regulation of gene expression by PKR following dsRNA treatment. In addition by identifying the signaling pathways involved in the regulation of three novel dsRNA induced PKR dependent genes, new insights have been provided into the role of this important kinase in regulating innate immunity.
Bryan Williams (Advisor)
208 p.
Biology, Molecular
PKR; IL-10; c-jun; egr-1; immediate early genes

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Citations

  • Chakrabarti, A. (2007). PKR DEPENDENT UPREGULATION OF IMMEDIATE EARLY GENES AND ANTI-INFLAMMATORY CYTOKINE IL-10 [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176136341

    APA Style (7th edition)

  • Chakrabarti, Arindam. PKR DEPENDENT UPREGULATION OF IMMEDIATE EARLY GENES AND ANTI-INFLAMMATORY CYTOKINE IL-10. 2007. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1176136341.

    MLA Style (8th edition)

  • Chakrabarti, Arindam. "PKR DEPENDENT UPREGULATION OF IMMEDIATE EARLY GENES AND ANTI-INFLAMMATORY CYTOKINE IL-10." Doctoral dissertation, Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1176136341

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.