Date of Completion

5-7-2016

Embargo Period

1-5-2016

Keywords

RKIP, T cells, B cells, PAMPs, MAPK, IFNg, Type I IFN, RNAseq, Proteomics, Signaling

Major Advisor

Anthony Vella

Associate Advisor

Robert Clark

Associate Advisor

Lynn Puddington

Associate Advisor

T.V. Rajan

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The studies presented here were designed to test if Raf-1 kinase inhibitor protein (RKIP) plays a functionally significant role in immunity, and to interrogate its possibility of providing a novel therapeutic target for modulating inflammatory responses. Based on previous studies from other laboratories that attributed negative regulatory functions to RKIP in the context of MAPK and NF-κB signaling in cell lines, we tested the hypothesis that its function was to suppress the production of pro-inflammatory cytokines, proliferation, and cell survival. However, after extensive investigation, our data clearly demonstrate that RKIP is actually necessary for the production of certain cytokines, namely Type-I and Type-II interferons, but had less robust effects on cell survivability and proliferation. Specifically, this work shows that RKIP is integrated in the signaling pathway downstream of TCR triggering in CD8+ T cells and TLR ligation in APCs. Finally, these studies highlight RKIP as a druggable protein, and through its targeted inhibition, cytokine responses can be significantly diminished. Thus, this provides elementary rationale for its potential clinical applicability in therapeutic interventions for inflammatory diseases, especially those associated with dysregulated IFN responses. Through this current work, we have provided a solid foundation for future studies that seek to investigate further the molecular mechanisms of RKIP function within the immune system, as well as its advancement into clinically relevant inflammatory disease models.

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