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The Anti-Inflammatory Mechanisms of the Flavonoid Apigenin In Vitro and In Vivo

Nicholas, Courtney

Abstract Details

2009, Master of Science, Ohio State University, Molecular, Cellular, and Developmental Biology.
The cells of the innate immune system are responsible for an organism’s first line of defense against various pathogens. Cells such as macrophages and neutrophils are capable of detecting the presence of a bacterial, viral, fungal, or protozoan pathogen through specialized Toll-like receptors on the plasma membrane. These receptors, when activated, initiate an inflammatory response mediated by various kinases, catalytic and regulatory proteins, and ubiquitin ligases, resulting in the activation of several transcription factors, including NF-κB. It is through this signaling cascade that the cells are able to initiate phagocytosis to destroy the pathogen, and release pro-inflammatory cytokine molecules to activate other immune cells and propagate the immune response. However, unregulated inflammation results in several serious human inflammatory diseases including sepsis and sepsis-related disorders such as acute lung injury. Several decades of failed clinical trials have led to the search for alternative therapies. Flavonoids, a class of polyphenolic plant compounds, are reported to be potent anti-inflammatory agents in vitro and in vivo, but their molecular and physiological mechanisms are still largely unknown. Apigenin is a member of the flavonoid family, and has similarly demonstrated anti-inflammatory properties. In these experiments it is shown that apigenin inhibits transcriptional activation of NF-κB and subsequent release of pro-inflammatory cytokines TNFα, IL-1β, and IL-8 in response to bacterial lipopolysaccharide (LPS) stimulation. Apigenin did not modulate degradation of the NF-κB inhibitor IκB or interfere with binding of NF-κB with DNA. However, apigenin modulated phosphorylation of NF-κB’s p65 subunit via indirect inhibition of the IKKβ kinase. Apigenin was effective in reducing TNFα production mediated by several different Toll receptor ligands. Naringenin (a structurally similar compound), as well as glycosylated forms of apigenin failed to modulate inflammatory response, and glycosylated apigenin was not able to enter cells in vitro. In a mouse model of sepsis –related acute lung injury, intraperitoneal apigenin rescued LPS-induced mortality, improved cardiac function, and reduced TNFα in serum. Apigenin failed to modulate cell death in spleens, which is traditionally shown to correlate with sepsis-related death in humans and mice. However, apigenin decreased neutrophil infiltration, cell death, expression of chemotactic proteins in mouse lungs, and chemotactic response in human neutrophils in vitro. Apigenin was detected with no metabolic modifications in mouse liver and urine. This work further illuminates apigenin’s molecular and physiological mechanisms, highlights apigenin’s potential as an anti-inflammatory therapy, and suggests novel therapeutic targets in the signaling cascade of bacterial-mediated inflammatory disorders.
Andrea Doseff (Advisor)
Erich Grotewold (Committee Member)
Mark Parthun (Committee Member)
126 p.

Recommended Citations

Citations

  • Nicholas, C. (2009). The Anti-Inflammatory Mechanisms of the Flavonoid Apigenin In Vitro and In Vivo [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259783472

    APA Style (7th edition)

  • Nicholas, Courtney. The Anti-Inflammatory Mechanisms of the Flavonoid Apigenin In Vitro and In Vivo. 2009. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1259783472.

    MLA Style (8th edition)

  • Nicholas, Courtney. "The Anti-Inflammatory Mechanisms of the Flavonoid Apigenin In Vitro and In Vivo." Master's thesis, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1259783472

    Chicago Manual of Style (17th edition)