Pre-treatment with IL-6 potentiates β-cell death induced by pro-inflammatory cytokines

Background Type I Diabetes mellitus (T1D) is characterized by a specific destruction of beta-cells by the immune system. During this process pro-inflammatory cytokines are released in the pancreatic islets and contribute for beta-cells demise. Cytokine-induced iNOS activation, via NF-kappa B, is implicated in induction of beta-cells death, which includes ER stress activation. Physical exercise has been used as an adjunct for better glycemic control in patients with T1D, since it is able to increase glucose uptake independent of insulin. Recently, it was observed that the release of IL-6 by skeletal muscle, during physical exercise, could prevent beta-cells death induced by pro-inflammatory cytokines. However, the molecular mechanisms involved in this beneficial effect on beta-cells are not yet completely elucidated. Our aim was to evaluate the effect of IL-6 on beta-cells exposed to pro-inflammatory cytokines. Results Pre-treatment with IL-6 sensitized INS-1E cells to cytokine-induced cell death, increasing cytokine-induced iNOS and Caspase-3 expression. Under these conditions, however, there was a decrease in cytokines-induced p-eIF2-alpha but not p-IRE1expression, proteins related to ER stress. To address if this prevention of adequate UPR response is involved in the increase in beta-cells death markers induced by IL-6 pre-treatment, we used a chemical chaperone (TUDCA), which improves ER folding capacity. Use of TUDCA increased cytokines-induced Caspase-3 expression and Bax/Bcl-2 ratio in the presence of IL-6 pre-treatment. However, there is no modulation of p-eIF2-alpha expression by TUDCA in this condition, with increase of CHOP expression. Conclusion Treatment with IL-6 alone is not beneficial for beta-cells, leading to increased cell death markers and impaired UPR activation. In addition, TUDCA has not been able to restore ER homeostasis or improve beta-cells viability under this condition, suggesting that other mechanisms may be involved.