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Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses

Kannan, Yashaswini

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2011, Doctor of Philosophy, Ohio State University, Biophysics.

Innate immunity primarily mediated by germline-encoded pathogen recognition receptors (PRRs), recognize the pathogen and activate immune signaling. Signaling mediated by the innate immune toll like receptors (TLRs), culminates in the downstream activation of the transcription factor, nuclear factor κB (NFκB), which activates the expression of pro-inflammatory cytokines and other mediators that coordinately amplify the immune response to defend the host against the pathogen.

Unlike most IκB family proteins, the NFκB regulators, IκBζ is an activator of pro-inflammatory gene expression. IκBζ, the protein product of the NFKBIZ primary response gene, is induced rapidly in response to toll-like/interleukin (IL)-1 receptor signaling in monocytes and macrophages. It is a nuclear protein, which is important in the transcriptional regulation of pro-inflammatory, secondary response genes like IL-6, IL-12 (p40), IL-18, granulocyte macrophage colony stimulating factor (GMCSF), neutrophil gelatinase associated lipocalin (NGAL) and human β-defensin 2 (hBD2). This report focuses on the functional characterization of human IκBζ with specific focus on its role as a transcriptional regulator of pro-inflammatory gene expression.

The discussions begin with the regulation of IL-6 expression by the two isoforms of human IκBζ namely, IκBζ-L and IκBζ-S in chapter 2. We demonstrate, the previously unevaluated, identical functions for the two isoforms of IκBζ. Our studies suggest IκBζ-L and IκBζ-S are post-transcriptionally regulated in response to IL-1β. These experiments provide a detailed insight on the expression and function of IκBζ, thus helping understand the role of the IκBζ-L and IκBζ-S in innate immune signaling.

In chapter 3 we report for the first time, transcriptional regulation mediated by IκBζ towards IFN-γ expression in human NK cells in response to IL-12 and IL-18. Our studies indicate IκBζ binds the IFNG promoter and activates gene expression at the promoter. Additionally we demonstrate the co-regulation of this IκBζ mediated regulation of IFN-γ production by, NFκB. This study emphasizes and expands the role of IκBζ as a global regulator of inflammatory genes in innate immune cells.

The discussion in Chapter 4 evaluates IκBζ expression along with other key pro-inflammatory mediators in response to the atherosclerotic mediator oxidatively modified LDL (oxmLDL). Since inflammatory signaling is central to the pathophysiology of atherosclerosis, we focus on the functional significance of oxmLDL in regulating TLR signaling leading to the production of pro-inflammatory cytokines and mediators. Our studies indicate the lack of a significant role of oxmLDL in activating pro-inflammatory signaling but a suppressive function of the lipoprotein upon addition to TLR ligand activated human monocytes, thus highlighting the role of lipoproteins in modulating the inflammatory microenvironment in an in vitro model of atherosclerosis.

The discussion ends in chapter 5, which provides a summary of the findings, highlighting the main conclusions and contrasting the differences in IκBζ’s function as a transcriptional regulator of IL-6 and of IFN-γ. It also provides a brief perspective for future studies based on the evidence from literature and the current studies.

In conclusion, this report highlights the significance of IκBζ as a global regulator of inflammatory gene expression providing insights into the mechanistic details of its function.

Mark Wewers, M.D. (Advisor)
Kathleen Boris-Lawrie, PhD. (Committee Member)
Susheela Tridandapani, PhD. (Committee Member)
Denis Guttridge, PhD. (Committee Member)
187 p.

Recommended Citations

Citations

  • Kannan, Y. (2011). Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1314564642

    APA Style (7th edition)

  • Kannan, Yashaswini. Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1314564642.

    MLA Style (8th edition)

  • Kannan, Yashaswini. "Functional Characterization Of Human IkappaBzeta In Modulating Inflammatory Responses." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1314564642

    Chicago Manual of Style (17th edition)