Effect of Heparin on the Immunobiology of Interleukin-12 Public Deposited

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  • March 20, 2019
Creator
  • Nguyen, Khue
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • IL-12 is a potent pro-inflammatory cytokine that plays a central role in cellular immunity. Recently, we have shown that IL-12 is a specific heparin-binding protein. However, the interaction of heparin and IL-12 at the molecular level and the mechanisms by which heparin modulates the biological functions of IL-12 are unknown. For the first time, we described the unique ability of heparin to enhance the bioactivity of IL-12. Heparin was found to enhance binding of IL-12 to cell surfaces while modestly protecting the cytokine from proteolytic degradation. An exploration of critical heparin characteristics revealed that IL-12 binding and activity increased were dependent on heparin chain length and sulfation level. Based on our bioactivity data, we developed a model of stabilization showing that heparin likely serves as a co-receptor that enhances the interaction of IL-12 with its subunit receptors. Finally, we examined the effect of heparin on IL-12 bioactivity in IL-12RB1 deficient cells. In both PBMCs isolated from patients of Mendelian susceptibility to mycobacterial diseases (MSMD) and IL-12RB1 mutant NK-92MI cell line, heparin was found to partially recover IL-12 signaling as measured via IFN-gamma production. Taken together, these studies define a new role for heparin as a modulator of the immunobiology of IL-12 and potentially other IL-12 family cytokines.
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Rights statement
  • In Copyright
Advisor
  • Whitmire, Jason
  • Liu, Jian
  • Zaharoff, David
  • Tisch, Roland
  • Wan, Yisong
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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