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Molecular analysis of the role of Fcγb, SHIP and PI 3-kinase in macrophage Fcγ receptor function

Joshi, Trupti Prabhakar
http://rave.ohiolink.edu/etdc/view?acc_num=osu1180983336

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Fcγ Receptors expressed on macrophages are engaged and activated by immune-complexes (ICs). This activation leads to elimination of ICs via the process of phagocytosis along with the release of inflammatory mediators. FcγR-mediated phagocytic process is tightly regulated by simultaneous engagement of activating and inhibitory Fcγ receptors and by the activation of various kinases and phosphatases. In this study we have examined the molecular details of regulation of FcγR functions by the inhibitory FcγRIIb, the inositol phosphatase SHIP-1 and the phosphatidylinositol 3-kinase (PI 3-Kinase). In the first part of this dissertation, we tested the functional differences between the two isoforms of human FcγRIIb, b1 and b2, in macrophages. The results of these experiments revealed that both FcγRIIb1 and FcγRIIb2 are equivalently surface expressed, undergo tyrosine phosphorylation upon activation and induce the phosphorylation of SHIP-1. Both FcγRIIb1 and FcγRIIb2 downregulate phagocytosis and TNFα production to a similar extent. Together these findings demonstrate that hFcγRIIb1 and b2 are both functional inhibitory receptors in the phagocytic process. In the second part, we examined the influence of inositol phosphatase SHIP-1 on phagocytosis-associated events and show for the first time that SHIP-1 negatively regulates FcγR-induced production of IL-1β and IL-6 and superoxide generation in macrophages. Analysis of the molecular mechanisms of regulation established that SHIP-1 regulates the activation of PI 3-kinase and Ras/Erk pathway upstream of IL-1β and IL-6 production and the activation of Rac upstream of superoxide production. Interestingly, the modulation of the PI 3-kinase pathway by SHIP-1 is dependent on its catalytic activity whereas the regulation of the Ras/Erk pathway is independent of SHIP-1’s catalytic activity. In the last part of this dissertation, we investigated the molecular mechanisms involved in the process of macrophage-mediated ADCC. We show for the first time that activation of the PI 3-kinase/Akt pathway plays a critical role in macrophage-mediated ADCC against B cell lymphoma cells. We further demonstrate that the PI 3-kinase/Akt pathway regulates macrophage-mediated ADCC through its influence on cytoskeletal remodeling during the conjugate formation stage. Taken together these findings provide novel insights into the regulation of the phagocytic process by FcγRIIb and inositol phosphatase SHIP-1 and regulation of macrophage-mediated ADCC by the PI 3-kinase/Akt pathway.
Susheela Tridandapani (Advisor)
165 p.
Fc receptors; macrophages; phagocytosis; ADCC; SHIP; PI 3-kinase

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Citations

  • Joshi, T. P. (2007). Molecular analysis of the role of Fcγb, SHIP and PI 3-kinase in macrophage Fcγ receptor function [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180983336

    APA Style (7th edition)

  • Joshi, Trupti. Molecular analysis of the role of Fcγb, SHIP and PI 3-kinase in macrophage Fcγ receptor function. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1180983336.

    MLA Style (8th edition)

  • Joshi, Trupti. "Molecular analysis of the role of Fcγb, SHIP and PI 3-kinase in macrophage Fcγ receptor function." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180983336

    Chicago Manual of Style (17th edition)

osu1180983336
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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.