Indiana University-Purdue University Indianapolis (IUPUI) / Platelet-activating Factor (PAF) stimulates various cell types by the activation of
the G-protein coupled PAF-receptor (PAFR). Systemic PAFR activation induces an acute
pro-inflammatory response, as well as delayed systemic immunosuppressive effects in
vivo. De novo enzymatic PAF synthesis and degradation are closely regulated, but
oxidative stressors, such as UVB, and cigarette smoke, can generate PAF-like species via
the oxidation of membrane lipids in an unregulated process. Mast cells (MCs) and the
PAFR have been shown to be necessary to mediate the resulting systemic immune
suppression from oxidative stressors. The work herein implicates pro-oxidative
chemotherapeutics, such as melphalan and etoposide, in mediating augmentation in tumor
growth by inducing the generation of PAFR agonists via the oxidation of membrane
lipids. This work also demonstrates the role of MCs and MC-released mediators in PAFR
systemic immunosuppression. Through a contact hypersensitivity (CHS) model, the MC
PAFR was found to be necessary and sufficient for PAF to mediate systemic
immunosuppression. Additionally, activation of the MC PAFR seems to induce MC
histamine and prostaglandin E2 release. Furthermore, by transplanting histamine- or
COX-2-deficient MCs into MC-deficient mice, MC-derived histamine and prostaglandin
release were found to be necessary for PAF to induce systemic immunosuppression. Lastly, we have evidence to suggest that prostaglandin release modulates MC migration
to draining lymph nodes, a process necessary to promote immunosuppression. These
studies fit with the hypothesis that MC PAFR activation mediates PAFR systemic
immunosuppression in part by histamine and prostaglandin release.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10614 |
| Date | 02 May 2016 |
| Creators | Ocaña, Jesus Alejandro |
| Contributors | Safa, Ahmad R., Travers, Jeffrey B., Kaplan, Mark H., Lu, Tao, Zhang, Jian-Ting |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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