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THE FUNCTION OF INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE 2 IN TOLL-LIKE RECEPTOR-MEDIATED SIGNALING

Wan, Youzhong

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Genetics.
Toll-like receptors (TLRs), important pathogen recognition receptors that mediate innate immune responses against infections, detect the invading pathogens through pathogen associated molecular patterns, and then induce the production of proinflammatory cytokines and interferons through a variety of signaling cascades. Although proinflammatory cytokines and interferons are essential for eliminating the pathogens, aberrant activation of TLR–mediated signaling has been implicated in many autoimmune diseases and chronic inflammation. Dissecting the molecular mechanisms of TLR-mediated signaling will not only improve our understanding of innate immune responses but also provide rationales for the development of effective treatments for infectious and autoimmune diseases. The function of interleukin-1 receptor associated kinase 2 (IRAK2) in TLR-mediated signaling is investigated in this dissertation. Although IRAK2 deficiency leads to decreased production of proinflammatory cytokines in multiple TLR-mediated signaling pathways, the mechanisms involved are not all the same. In TLR4-mediated signaling, IRAK2 is required for stabilizing proinflammatory cytokine mRNAs and promoting their translation. In TLR7-mediated signaling, IRAK2 is essential for sustaining the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) at late times of stimulation. While IRAK2 is also essential for sustaining NFκB activation in TLR9-mediated signaling at late times of stimulation, IRAK2 deficiency leads to increased activation of multiple signaling cascades downstream of TLR9 at early times. Strikingly, increased activation of interferon regulatory factor 7 leads to increased interferon production in IRAK2-deficient plasmacytoid dendritic cells stimulated with TLR9 ligand. Compared to signaling mediated by other TLRs, TLR9-mediated signaling is controlled by IRAK2 more tightly, most likely to prevent immune responses caused by inappropriate recognition of host DNA. The studies presented here, which have examined the function of IRAK2 in different TLR-mediated signaling pathways, can aid in the identification of new therapeutic targets and advance our understanding of innate immune responses.
George Stark (Advisor)
Ronald Conlon (Committee Chair)
Joseph Nadeau (Committee Member)
Xiaoxia Li (Committee Member)

Recommended Citations

Citations

  • Wan, Y. (2010). THE FUNCTION OF INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE 2 IN TOLL-LIKE RECEPTOR-MEDIATED SIGNALING [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1278430683

    APA Style (7th edition)

  • Wan, Youzhong. THE FUNCTION OF INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE 2 IN TOLL-LIKE RECEPTOR-MEDIATED SIGNALING. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1278430683.

    MLA Style (8th edition)

  • Wan, Youzhong. "THE FUNCTION OF INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE 2 IN TOLL-LIKE RECEPTOR-MEDIATED SIGNALING." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278430683

    Chicago Manual of Style (17th edition)