Indiana University-Purdue University Indianapolis (IUPUI) / Heat shock protein (HSP) 90 is a molecular chaperone that regulates diverse
cellular processes by facilitating activities of various protein clients. Recent studies have
shown serum levels of the alpha cytoplasmic HSP90 isoform are elevated in newly
diagnosed type I diabetic patients, thus distinguishing this protein as a potential
biomarker for pre-clinical type I diabetes mellitus (TIDM). This phase of disease is known
to be associated with various forms of beta cell stress, including endoplasmic reticulum
stress, insulitis, and hyperglycemia. Therefore, to test the hypothesis that HSP90 is
released by these cells in response to stress, human pancreatic beta cells were
subjected to various forms of stress in vitro. Beta cells released HSP90 in response to
stimulation with a combination of cytokines that included IL-1β, TNF-α, and IFN-γ, as
well as an agonist of toll-like receptor 3. HSP90 release was not found to result from
cellular increases in HSP90AA1 gene or HSP90 protein expression levels. Rather, cell
stress and ensuing cytotoxicity mediated by c-Jun N-terminal kinase (JNK) appeared to
play a role in HSP90 release. Beta cell HSP90 release was attenuated by pre-treatment
with tauroursodeoxycholic acid (TUDCA), which has been shown previously to protect
beta cells against JNK-mediated, cytokine-induced apoptosis. Experiments here
confirmed TUDCA reduced beta cell JNK phosphorylation in response to cytokine stress.
Furthermore pharmacological inhibition and siRNA-mediated knockdown of JNK in beta
cells also attenuated HSP90 release in response to cytokine stress. Pharmacological
inhibition of HSP90 chaperone function exacerbated islet cell stress during the
development of TIDM in vivo; however, it did not affect the overall incidence of disease. Together, these data suggest extracellular HSP90 could serve as a biomarker for preclinical
TIDM. This knowledge may be clinically relevant in optimizing treatments aimed
at restoring beta cell mass. The goal of such treatments would be to halt the progression
of at-risk patients to insulin dependence and lifelong TIDM.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10633 |
| Date | 23 May 2016 |
| Creators | Ocaña, Gail Jean |
| Contributors | Blum, Janice Sherry, 1957-, Kaplan, Mark H., Serezani, C. Henrique, Sun, Jie |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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