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Title: The induction and effects of Substance P and its receptor in human immune cells and neurons : potential relevance in multiple sclerosis
Author: Vilisaar, Janek
ISNI:       0000 0004 2727 2524
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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INTRODUCTION: Substance P (SP) has well-established roles in neurogenic inflammation and pain transmission, however recently, a number of SP immunomodulatory effects have been shown. In this thesis SP and its neurokinin-1-receptor (NK1R) role in autoimmune inflammation was investigated with an applicability to multiple sclerosis (MS). In the four experimental chapters the role of SP and its receptor was studied in human immune cells and neurons with a focus on the relationship with Th17 and Th1 pathways as the main pro-inflammatory arms in autoimmune pathology. AIMS: To quantify the effects of SP on inflammatory cytokine induction in peripheral blood mononuclear cells (PBMC); to measure Th17 and Th1 pathway effects on SP and NK1R expression in T cells and NT2 neurons; to compare NK1R expression and relevant parameters in peripheral immune cells of relapsing-remitting MS patients and healthy controls. METHODS: Real-time PCR, flow cytometry, ELISA, Western blotting and promoter studies were used to measure the expression of target genes under different stimulation conditions. Cells were isolated from consented healthy controls, relapsing-remitting MS patients, or differentiated as specified. RESULTS: In PBMC, treatment with SP significantly increased the relative quantity of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA showing that SP can signal induction of IL-12 and IL-23. As part of the reciprocal mechanism in T cells, NK1R and SP expression was strongly upregulated by Th17 cytokines and significantly less by Th1 cytokines. These effects for NK1R were confirmed at promoter and protein levels. The Th17 effects were prevalent at earlier stages compared to the Th1 effects. As a novel finding, IL-17 (IL-17A) had direct effects on neurons via its functionally expressed receptor. Neuronal NK1R mRNA-level expression was subject to regulation by IL-17, whereas SP precursor was considerably less upregulated by IL-17. In MS patients in a relapse NK1R mRNA in peripheral immune cells was strongly downregulated as compared to controls. This finding is likely associated with the inflammatory activity in an acute MS relapse. CONCLUSIONS: Mutual interactions exist between SP and Th17, Th1 responses with SP showing involvement in Th17 and less in Th1 pathway effects. This supports NK1R role in mediating autoimmune activity as occurs in an acute MS relapse. The results also show direct neuronal involvement in immune interactions involving SP and Th17 pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QU Biochemistry