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Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease

Wancket, Lyn Miller

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Mitogen activated protein kinases (MAPKs, including ERK, JNK, and p38) are key regulators of numerous physiological and pathophysiological pathways and are activated by phosphorylation. MAPK activation is partially controlled via dephosphorylation by a class of endogenous inhibitors, the MAPK phosphatases (MKPs). MKP-1 is the prototypical member of the MKP family, and is recognized as playing an important role in regulating primarily p38 and JNK activation in a wide variety of disease states and animal models. Here, I both review the role of MKP-1 in host physiology and response to disease and report novel findings for the importance of MKP-1 at the level of cellular regulation, in organ-specific toxicities, and in models of pulmonary infection. First, in chapter one I provide an overview of the current literature concerning MKP-1, including basic biochemistry, mRNA and protein regulation, and currently known roles for how MKP-1 functions in both animal models of disease and human clinical conditions. Next, I outline my research findings that identify novel roles of Mkp-1 in cellular and whole animal models. In chapter two I report how Mkp-1 and its related MKP family member, Mkp-2, are induced in macrophages in response to lipopolysaccharide (LPS) treatment. These findings include identifying post-translational modifications that can alter Mkp protein stability and its recognition by antibodies. In chapter three, I demonstrate that Mkp-1 provides hepatocellular and host survival advantages in a mouse model of acute acetaminophen toxicity. In the following two chapters, I report how Mkp-1 functions in the innate pulmonary immune response to both viral and bacterial pathogens. In chapter four, I demonstrate that loss of Mkp-1 prolongs p38 activation in mouse macrophages, enhances cytokine release in vivo and in vitro, and exacerbates clinical signs in mice inoculated with a high dose of a mouse adapted influenza strain. Additionally, in chapter five I describe a novel model of primary Streptococcus pneumoniae infection in mice in which Mkp-1 deficient mice have reduced mortality compared to wildtype mice. Finally, in chapter six, I summarize our novel findings and place them within the context of the literature. Additionally, I will describe avenues for future research, including a potential role for MKP-1 in regulating the pulmonary response to allergens. In summary, our studies demonstrate that MKP-1’s suppression of MAPK activation and downstream cytokine release is vital when responding to acute hepatotoxic or pulmonary viral injury, but limiting inflammation may be harmful when rapid and localized containment is needed to prevent a systemic septic event
Yusen Liu (Advisor)
221 p.

Recommended Citations

Citations

  • Wancket, L. M. (2013). Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385390100

    APA Style (7th edition)

  • Wancket, Lyn. Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease . 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385390100.

    MLA Style (8th edition)

  • Wancket, Lyn. "Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology, and disease ." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385390100

    Chicago Manual of Style (17th edition)