Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


case1182005526.pdf (5.04 MB)

ETD Abstract Container

Abstract Header

REGULATION OF dsRNA-INDUCED TRANSCRIPTION BY NFêB AND IRF-3 THROUGH TLR3 AND RIG-I

Elco, Christopher
http://rave.ohiolink.edu/etdc/view?acc_num=case1182005526

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Molecular Virology.
dsRNA is an important regulator of gene induction. The cellular response to dsRNA is mediated through either toll-like receptor 3 (TLR3) or the RNA helicases, RIG-I and mda5. While TLR3 and RIG-I/mda5 recognize dsRNA in different cellular compartments, both can signal to activate the transcription factors IRF-3 and NFêB. Both transcription factors, in turn, regulate the expression of hundreds of genes. This dissertation contains the following contributions to the field of dsRNA signaling: 1) Sendai virus, a negative-strand RNA virus, does not induce cellular genes through TLR3, rather RIG-I is required for the induction of ISG56 by SeV. In contrast, adding dsRNA to the culture media leads to only TLR3-mediated gene induction. 2) STAT1-null, U3A cells do not respond to dsRNA added to the media as the result of low TLR3 expression. Expression of STAT1 in U3A cells allows them to respond to interferon, but not dsRNA. However, pre-treatment of STAT1-restored U3A cells with interferon-β or interferon-γ induces TLR3 expression, and makes the cells responsive to dsRNA. This result shows that stimulation with interferons, by inducing TLR3, can make cells, otherwise unresponsive to dsRNA, responsive. 3) By microarray analysis, which dsRNA and Sendai virus-induced genes are regulated by IRF-3 or by NFêB were determined. Genes induced indirectly by dsRNA signaling, either dependent upon or independent of autocrine IFN signaling were also identified. Finally, the PI3K inhibitor LY blocks TLR3-mediated induction of IRF-3 but not NFêB-dependent genes, thus showing that unlike IRF-3 dependent gene induction, NFκB-dependent induction through TLR3 does not require PI3K. 4) IRF-3 inhibits the expression of a subset of genes normally induced by SeV and dsRNA. The degree to which SeV-induced gene expression is inhibited is inversely proportional to the expression level of IRF-3. The inhibitory effects of IRF-3 are independent of its transcriptional activation, as gene induction by TNF-α, which does not activate IRF-3, is also inhibited. Although many of the genes negatively regulated by IRF-3, including A20, c-IAP1, c-IAP2, and TRAF1, are NFκB-dependent, IRF-3 does not inhibit NFκB activation. In total these results add to the understanding of the complexities of dsRNA-mediated gene induction.
Ganes Sen (Advisor)
IRF-3; dsRNA; TLR3; ISG56; GENE; SeV; NF¿¿¿¿B

Recommended Citations

Citations

  • Elco, C. (2007). REGULATION OF dsRNA-INDUCED TRANSCRIPTION BY NFêB AND IRF-3 THROUGH TLR3 AND RIG-I [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1182005526

    APA Style (7th edition)

  • Elco, Christopher. REGULATION OF dsRNA-INDUCED TRANSCRIPTION BY NFêB AND IRF-3 THROUGH TLR3 AND RIG-I. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1182005526.

    MLA Style (8th edition)

  • Elco, Christopher. "REGULATION OF dsRNA-INDUCED TRANSCRIPTION BY NFêB AND IRF-3 THROUGH TLR3 AND RIG-I." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1182005526

    Chicago Manual of Style (17th edition)

case1182005526
861
© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.