Title page for ETD etd-05102010-061531


Type of Document Dissertation
Author Gan, Lu
URN etd-05102010-061531
Title The Involvement of Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1) as a Critical Modulator of Macrophage Migration
Degree PhD
Department Biology
Advisory Committee
Advisor Name Title
Li, Liwu Committee Chair
Hulver, Matthew W. Committee Member
Lawrence, Christopher B. Committee Member
Lee, Yong Woo Committee Member
Keywords
  • IRAK
  • innate immunity
  • actin regulatory protein
  • chemokine
  • macrophage migration
Date of Defense 2010-04-26
Availability unrestricted
Abstract
Macrophage migration, an essential component of many biological processes and pathologic conditions, is mediated by integrated cellular signaling processes and cytoskeleton rearrangement. Recent advances indicate that the innate immunity signaling process plays a key role in the regulation of macrophage migration.

Furthermore, our lab has provided evidence demonstrating the involvement of a key innate immunity signaling kinase, IRAK-1, as a critical modulator of murine macrophage migration. Macrophage migration induced by a potent PKC activator, phorbol 12-myristate 13-acetate (PMA), or lipopolysaccharide (LPS) was significantly decreased in IRAK-1-/- murine macrophages compared with wild type cells. Mechanistically, we first demonstrated that IRAK-1 works downstream of PKCepsilon and directly binds to VASP, a cytoskeleton regulatory protein, to regulate PMA-induced macrophage migration. Secondly, we proved that IRAK-1 is required for LPS-induced macrophage migration and expression of MCP-1, a chemotactic cytokine for macrophages, via transcription factor C/EBPdeltainstead of NFkB. IRAK-1 binds directly to IKKepsilon and inhibition or knock-down of IKKepsilon results in a significant decrease in C/EBPdelta expression and MCP-1 mRNA expression. Lastly, we identified the direct association between IRAK-1 and Rac1, a member of the Rac subfamily in the Rho family of GTPases. These finding further confirmed the essential role of IRAK-1 during macrophage migration. Our research provides a novel facet regarding the molecular signaling processes regulating macrophage migration.

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