Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

Abstract

Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes ,, , A20 and and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.

Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells

“…In the present study, we demonstrated that the JNK pathway was profoundly activated in β cells by proinflammatory cytokines and oxidative stress. This does not contradict the findings that demonstrated the role of both NF- κ B and JNK signaling in rat β cell death that is induced by proinflammatory cytokines [ 42 ]. Interestingly, PRDX6 downregulated the JNK activity in β cells exposed to TNF- α and IL-1 β , suggesting that oxidative stress and subsequent activation of the JNK pathway could be involved in the pathogenesis of T1D.…”

Loss of Caveolin-1 Is Associated with a Decrease in Beta Cell Death in Mice on a High Fat Diet

“…Additionally, CAV1 overexpression induced the activation of ERK, JNK and p38 signaling pathways in Hepa1-6 cells [ 57 ]. MAPKs have been associated with both anti- [ 58 , 59 , 60 ] and pro-apoptotic [ 18 , 19 , 20 , 21 , 22 , 23 , 61 ] effects in beta cells. Currently, the prevalent notion is that JNK and p38 activation induced by FFAs in beta cells is pro-apoptotic, while ERK1/2 activation is considered more anti-apoptotic [ 62 ].…”

“…Whether these responses protect against cell demise or, conversely, promote stress-induced cell death, appears to be cell context-dependent [ 17 ]. Activation of these MAPK pathways in response to cellular stress has been implicated in apoptotic-signaling responsible for beta cell loss [ 18 , 19 , 20 , 21 , 22 , 23 ]. CAV1 has been linked to the regulation of MAPKs by either activating or inhibiting these kinases, with different consequences concerning cell viability.…”

The effect of prolactin concentration on the efficacy of storing isolated porcine kidneys in a modified Biolasol solution

“…Moreover, Yamamoto et al suggest that rhPRL has a cytoprotective effect on the islets of Langerhans, which may improve the survival of pancreatic grafts [29]. It may result from the participation of PRL in the anti-apoptotic mechanism and reduction of pro-apoptotic effectors, and consequently, protect cells against inflammation [30].…”