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Publication Date

2015-04-29

Availability

UM campus only

Embargo Period

2015-04-29

Degree Name

Master of Science (MS)

Department

Psychology (Arts and Sciences)

Date of Defense

2015-04-01

First Committee Member

Philip M. McCabe

Second Committee Member

Armando J. Mendez

Third Committee Member

Neil Schneiderman

Abstract

Social environment influences the progression of atherosclerosis, a chronic inflammatory process. Oxytocin (OT) has been associated with pro-social behavior; however, plasma OT levels are not elevated in a pro-social environment in animal models of disease. Infusion of exogenous OT in these disease models attenuates inflammation and arterial plaque, which raises the possibility that OT’s anti-inflammatory effects may be regulated at the level of the OT receptor (OTR) rather than by changes in plasma OT titers as a function of social environment. The current study investigated OTR and signaling pathways in human macrophages to understand how inflammation affects the OT/OTR system at the molecular level. We hypothesized that OTR is an acute phase protein, whose expression is increased during the inflammatory response though a nuclear factor κB (NF-κB) mediated pathway. We further evaluated whether inflammation alters OTR signaling pathways, which can occur through either the phosphatidylinositol (PI) (Gαq/11) or the cAMP (Gαs) pathways. Inflammation was induced by treating THP-1 macrophages with lipopolysaccharide (LPS) and monitored by expression of the inflammatory cytokine, interleukin-6 (IL-6). Cells were treated with exogenous IL-6 and NF- κB inhibitor and OTR gene expression was measured by RT-PCR. OTR signaling was evaluated by phosphorylation of downstream targets, ERK1/2 from the PI pathway, and CREB from the cAMP pathway, by immunoblotting after LPS and OT treatments. Induction of inflammation by LPS stimulation of macrophages significantly up-regulated OTR transcription 150-fold relative to control cell, however IL-6 had no effect on OTR expression. Blocking NF-κB activation prevented the increase in OTR transcription. Our data also confirmed OT-treatment of macrophages inhibits LPS stimulated IL-6 secretion. Incubation of LPS-treated cells with OT caused increased phosphorylation of ERK1/2 and CREB. Individual blocking of Gαq/11 and Gαs RNA resulted in a loss of OT’s ability to down-regulate IL-6. Together these results demonstrate receptor function through both Gαq/11 and Gαs signaling pathways during inflammation. OTR is an acute phase protein, whose expression can be regulated by NF-κB. Current data suggest both the PI and cAMP signaling pathways are activated by OTR during an inflammatory response and that the receptor may be responsible for attenuating the inflammatory response of the macrophage. This study is the first to demonstrate OT's effect on the non-conventional cAMP signaling pathway in this cell line and the importance of OTR in regulating inflammation. This suggests OTR regulation/function should be considered in addition to measurement of plasma OT.

Keywords

Oxytocin Receptor; Oxytocin; Inflammation; Acute Phase Protein; Signaling Pathway

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