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Envolvimento da prolactina na prevenção da disfunção e morte de células beta pancreáticas induzidas por citocinas pró-inflamatórias

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Author(s):
Tarlliza Romanna Nardelli
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
Defense date:
Examining board members:
Antonio Carlos Boschero; Letícia Labriola; Helena Cristina Barbosa Sampaio; Rodrigo Ferreira de Moura; Eliana Pereira de Araujo
Advisor: Antonio Carlos Boschero
Abstract

Type I diabetes is caused by an autoimmune assault that induces progressive ?-cell dysfunction and apoptosis. Pro-inflammatory cytokines (CYT) such as interleukin-1? (IL-1?), tumor necrosis factor-? (TNF-?) and interferon-? (IFN-?), contribute to ?-cell death, at least partly via activation of the transcription factor nuclear factor-?B (NF-?B). Prolactin (PRL) is an important mediator for the increase of ?-cell mass and has been reported to protect insulin-producing cells against CYT-induced apoptosis. We have presently investigated the potential protective effects of PRL against cytokine-induced ?-cell death and the mechanisms involved in this protection. Cell viability, NO measurement and protein expression in INS-1E cells were performed after a 24 h pretreatment with PRL (0.5?g/mL) or vehicle and subsequent 24 h exposure to IL-1? (10 U/mL) or TNF-? (1600 U/mL) in combination with IFN-? (140 U/mL), with or without the knockdown of STAT3. INS-1E cells exposed to IL-1?+IFN-? were also used for western blot and NF-?B promoter reporter assay in time course studies. Comparisons between groups were carried out either by unpaired t test or ANOVA followed by Bonferroni correction. A P value <0.05 was considered significant (n=4-6). After 24 h exposure, both IL-1?+IFN-? and TNF-?+IFN-? increased apoptosis by 1.5-fold in INS-1E cells. This was partially prevented by PRL (30%). The protection induced by PRL is, at least partly, mediated by STAT3, since it was almost abolished when STAT3 was inhibited by two specifics siRNA. Importantly, PRL also decreases JNK phosphorylation and modulates expression of anti- and pro-apoptotic proteins involved in JNK cascade by decreasing the expression of both p-c-JUN and dp5, and increasing BCL-XL expression. These signals converge to decrease PUMA expression and potentially beta cell loss. Moreover, PRL partially prevents the activation of NF-?B, affecting the expression of its target genes, which are involved in both, beta cell death and inflammation. Thus, PRL exerts a protective effect against CYT-induced ?-cell death. This is mediated at least in part via STAT3 activation, differential modulation of anti and pro-apoptotic proteins of BCL-2 family and decreased activation of NF-?B (AU)

FAPESP's process: 11/22852-3 - Involvement of prolactin in the prevention of beta cells dysfunction and death induced by endoplasmic reticulum stress
Grantee:Tarlliza Romanna Nardelli
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)