Title: Molecular Signaling Network Regulating Innate Immunity

Presenter: Dr. Liwu Li
    Department of Biological Sciences, Virginia Tech

Date and Time: Monday, November 13, 2006, 3:00-4:00PM

Abstract:
The human or mammalian host maintains a finely-regulated innate immunity signaling network, which can be quickly turned on and off. Quick activation enables the host to mount an efficient defense against infections or other challenges. On the other hand, timely deactivation of innate immunity signaling helps to prevent excessive inflammation and damage to the host. We have found that Tollip and IRAK-M serve as selective deactivators of Toll-like receptor (TLR)-mediated innate immunity signaling processes leading to the activation of transcription factor NFkB p65/RelA. p65/RelA is one of the key transcription factors mediating the activation of innate immune responses. Its activation involves at least two distinct events triggered by multiple upstream pathways: one being the degradation of inhibitory IkBa and subsequent p65 translocation into nucleus; the other independent process being the phosphorylation of p65. Nuclear unphosphorylated p65 and phosphorylated p65 may differentially regulate expression of downstream genes. Intriguingly, we found that IRAK-M specifically turns off TLR ligand-induced IkBa degradation and p65 nuclear translocation without affecting TLR ligand-induced p65 phosphorylation. In contrast, we observed that Tollip selectively turns off TLR-mediated p65 phosphorylation and has no effect on IkBa degradation and p65 nuclear translocation. Although timely deactivations of innate immunity signaling pathways help to prevent excessive inflammation, these deactivation mechanisms may also be exploited by tumor cells to evade active immune surveillance. Indeed, we found that injection of transplantable tumor cells such as B16-F0 into wild type mice can cause large tumor growth. In contrast, we demonstrated that IRAK-M-/- mice have enhanced anti-tumor immune response and resist tumor growth. We therefore hypothesize that IRAK-M and Tollip are differentially targeting distinct upstream pathways leading to either IkBa degradation and p65 translocation, or p65 phosphorylation, and collectively contribute to switching off TLR-mediated NFkB activation. Furthermore, we hypothesize that deletion of these deactivators (IRAK-M and/or Tollip) may help boosting host anti-tumor immune response.
Seminar Location: The seminars are held at:
    Virginia Tech, Corporate Research Center
    1880 Pratt Drive, Building XV
    Seminar Room 2018, Second Floor
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