Chronic non-bacterial inflammation of the prostate is associated with multiple prostate diseases including chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS), benign prostatic hyperplasia (BPH), and prostate cancer. The multiplicity of associations between prostate diseases and inflammation provide a strong rationale for better understanding the origin and regulation of prostate inflammation. While the cause of prostate inflammation has not been conclusively determined, T cell specific autoimmunity has been linked to prostate inflammatory processes both clinically and in animal models. Thus, studies to define autoimmune prostate inflammation and its regulation are needed to provide a better understanding of the inflammatory process and to identify potential points of intervention to reduce or eliminate inflammation. We developed a novel transgenic mouse model expressing membrane bound ovalbumin exclusively on prostate epithelial cells to investigate prostate inflammatory processes and its regulation. Studies during the past funding period showed an important role for myeloid-derived suppressor cells (MDSC) in the regulation of prostate inflammation. MDSC were observed as the dominant cell type in the inflammatory infiltrate during the first 10- 14 days of the response. Inhibition of MDSC regulation of T cells enhanced inflammation. Notably, functional MDSC were observed to be localized to the inflamed prostate, whereas phenotypically identical cells in the spleen and liver were classified as precursor cells, setting the stage for differential identification of pathways linked to MDSC function. Preliminary data shown herein show that a novel peptide inhibitor of inflammation and MDSC function was identified that links MDSC function and inflammatory cytokine levels in prostate inflammation to the p38 signaling pathway. Moreover, the cationic amino acid transporter that functions to deliver L-Arg to MDSC was identified. Finally, data were generated demonstrating an elevation of MDSC in the peripheral blood of patients with CP-CPPS compared to controls, suggesting a role in human disease. These data provide a foundation for the hypothesis that cytokine production and T cell regulation by MDSC are central to prostate inflammation and its regulation. Further, localization of MDSC function to the site of inflammation provides a basis for differentially identifying additional pathways linked to MDSC function. Studies outlined in this application propose to further define the regulatory pathways of MDSC with the intent of developing novel approaches to controlling prostate inflammation both in the POET-3 model and clinical specimens from CP-CPPS patients. To this end the following specific aims are proposed.
Specific Aim 1. Define myeloid-derived suppressor cell pathways/molecules in the POET-3 model and clinical setting of CP-CPPS central to controlling prostate inflammation. Hypothesis: Understanding the cellular molecules/pathways controlling MDSC regulation of T cell responses and cytokine production will provide avenues for dissecting functional implications of MDSC in modulating prostate inflammation.
Specific Aim 2. Define the impact of myeloid-derived suppressor cell regulation on prostate inflammation and prostate histopathology. Hypothesis: Myeloid-derived suppressor cells, although present early and transiently, are central to the regulation of prostate inflammation through inhibition of T cell responses and control of cytokine production at the inflammatory site.
The studies outlined in this proposal focus on understanding the regulatory processes active in controlling prostate inflammation. Myeloid-derived suppressor cells were identified as important regulators and are the focus of the outlined studies. Gene array studies identified novel molecules and pathways that are important to the function of myeloid-derived suppressor cells. Studies outlined in the proposal focus on understanding the impact of modulating the identified molecules and pathways on suppressor function.
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|Haverkamp, Jessica M; Crist, Scott A; Elzey, Bennett D et al. (2011) In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol 41:749-59|