Biomedical Sciences ETDs

Publication Date

5-1-2013

Abstract

A critical mechanism in immune homeostasis is the ability to stop an ongoing inflammatory response once the inciting agent has been destroyed or neutralized. Failure to do so can lead to autoimmune disease. One mechanism the immune system utilizes to self regulate is the secretion of immunosuppressive cytokines. For example, the cytokine interleukin-10 (IL10) is a potent suppressor of numerous key immune cell populations. Among the cells that secrete IL10 are several subsets of the CD4+ T cell family. As CD4+ T cells are commonly found within diseased tissue in the setting of autoimmune disease, medications capable of inducing IL10 expression in local CD4+ T populations would be of great therapeutic interest. The small molecule G-1, an agonist directed against the membrane-bound estrogen receptor GPER, is known to attenuate the multiple sclerosis-like animal model EAE. However, its effects on CD4+ T cell populations were previously unknown. Using cultures of purified CD4+ T cells, we show that G-1 can elicit ERK-dependent expression of IL10. G-1 treated cultures secreted 3-fold more IL10, with no change in the proinflammatory cytokines IL17A, TNFα, and IFNy. Analysis of Foxp3 and RORyt expression demonstrated increased percentages of IL10+ cells in both the TH17 (RORyt+) and Foxp3+RORyt+ hybrid T cell compartments. We also show that, in mice, in vivo treatment with G-1 leads to increased IL10 secretion from splenocytes. These results demonstrate that G-1 acts directly on CD4+ T cells, and to our knowledge provide the first example of a synthetic small molecule capable of eliciting IL10 expression in TH17 or hybrid T cell populations. While G-1 treatment was not effective in a murine model of colitis, investigations of its effects in other T cell-based disease models are warranted.

Keywords

GPER, G-1, CD4+ T cells, interleukin-10, T(H)17 cells

Sponsors

NIH grants R01 CA116662, CA118743 and CA127731 (ERP), the IDIP T-32 Intramural Fellowship, grant number T32-AI007538-12, the Ruth Kirschtein National Research Service Award, grant number 1F30DK084648-01A1, and the MD/PhD fellowship from the BSGP and the Biomedical Research Education Program (BREP)

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Eric Prossnitz

Second Committee Member

Brian L. Hjelle

Third Committee Member

Mary F. Lipscomb

Fourth Committee Member

C. Richard Lyons

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