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Identification of signaling pathways important for Borrelia burgdorferi-elicited IL-10 production by macrophages and their effects on suppressing antigen presenting cell immune responses

Chung, Yutein
http://rave.ohiolink.edu/etdc/view?acc_num=mco1308753897

Abstract Details

2011, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
Borrelia burgdorferi (Bb) is a tick-borne bacterium from the family Spirochaetes that is the causative agent for Lyme disease. These bacteria are notable for their ability to evade host defenses and persist extra-cellularly, even though infection elicits potent innate and adaptive immune responses. We previously demonstrated that host interleukin 10 (IL-10), an anti-inflammatory cytokine important for controlling excess inflammation, plays an important role in suppressing the immune-clearance of Bb. We hypothesize antigen-presenting cells (APCs) such as bone-marrow macrophages (BMM) and dendritic cells (BMDC) produce high-levels of IL-10 immediately upon recognition of Bb and this dysregulated IL-10 level subsequently suppresses the elicitation of pro-inflammatory mediators by the APCs against Bb. We also hypothesize that the production of IL-10 by APCs such as BMMs utilizes signaling pathways that are distinct from Bb-elicited pro-inflammatory mediators. Our results demonstrated that both cultured BMM and BMDCs rapidly produce IL-10 upon Bb-stimulation and this IL-10 suppressed the production of pro-inflammatory cytokines (e.g. IL-12), chemokines, reactive oxygen species, phagocytosis, and surface marker upregulation. Our data also indicate that IL-10 production by BMMs in response to Bb is dependent on surfaceToll-like receptor 2 (TLR2) yet independent of Bb phagocytosis/internalization. While most Bb-elicited pro-inflammatory mediators are also TLR2-dependent, they require that Bb be internalized. Bb-elicited IL-10 production by BMMs is dependent on signaling pathways involving both phosphotidylinositol-3 kinase (PI3-kinase) and mitogen-activating protein kinase (MAP kinase). On the other hand, the elicitation of most pro-inflammatory responses from BMMs by Bb is independent of both PI3-kinase and MAP kinase. Overall, our findings indicate that Bb stimulates APCs to produce dysregulated IL-10 through unique signaling pathways from those that produce inflammatory mediators and that the amount of IL-10 that are produced are sufficient to suppress many APC immune mechanisms that are critical for controlling bacterial infections. The delineation of these IL-10 specific signaling mechanisms should identify pathways that could be targeted to better control the development of Lyme disease.
R. Mark Wooten (Advisor)
217 p.
Immunology; Microbiology
Borrelia burgdorferi; macrophages; dendritic cells; interleukin 10; IL-10; toll-like receptor 2 TLR2; phagocytosis; OspA, PI3-kinase; MAP kinase p38; ERK 1/2

Recommended Citations

Citations

  • Chung, Y. (2011). Identification of signaling pathways important for Borrelia burgdorferi-elicited IL-10 production by macrophages and their effects on suppressing antigen presenting cell immune responses [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1308753897

    APA Style (7th edition)

  • Chung, Yutein. Identification of signaling pathways important for Borrelia burgdorferi-elicited IL-10 production by macrophages and their effects on suppressing antigen presenting cell immune responses. 2011. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1308753897.

    MLA Style (8th edition)

  • Chung, Yutein. "Identification of signaling pathways important for Borrelia burgdorferi-elicited IL-10 production by macrophages and their effects on suppressing antigen presenting cell immune responses." Doctoral dissertation, University of Toledo, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1308753897

    Chicago Manual of Style (17th edition)

mco1308753897
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© 2011, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.