Inhibition of cytokine signaling in pancreatic beta-cells: Mechanisms of PPAR-gamma agonists

Autoimmune diabetes is characterized by the selective destruction of insulin-secreting beta-cells found within the pancreatic islets of Langerhans. The ability of beta-cells to release insulin in a glucose-responsive manner is essential to maintain whole body glucose homeostasis, and in the face of beta-cell death, patients with autoimmune diabetes must inject exogenous insulin for survival. The onset of diabetes is precipitated by insulitis and infiltration of inflammatory cells such as macrophages, T and B lymphocytes, and natural killer cells into the islets. Cytokines produced by these effector cells, specifically macrophage-derived interleukin (IL)-1 and T cell-derived interferon (IFN)-gamma, can bind directly to beta-cells to induce cellular dysfunction and ultimately cell death. IL-1 and IFN-gamma stimulate signaling pathways that culminate in the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) by beta-cells. NO mediates beta-cell dysfunction and degeneration in response to cytokines, in part, by inhibiting oxidative metabolism and inducing DNA damage.; The goal of these studies was to identify mechanisms that protect beta-cells from cytokine-mediated damage. In an effort to address these goals, we have identified peroxisome proliferator activated receptor (PPAR)-gamma ligands as one class of small molecules that inhibit cytokine signaling in beta-cells. We show that PPAR-gamma ligands prevent IL-1-stimulated nuclear factor (NF)-kB activation and IFN-gamma-stimulated signal transducers and activators of transcription (STAT)-1 activation in a time-dependent manner, and that the inhibition of IL-1 and IFN-gamma signaling correlates with expression of the stress inducible protein hsp 70. The protective actions of PPAR-gamma agonists are not mediated by hsp 70, as antisense depletion does not modulate the ability of these ligands to attenuate cytokine signaling. In addition, the inhibition of cytokine signaling by PPAR-gamma ligands does not require activation of the nuclear receptor PPAR-gamma. One mechanism by which PPAR-gamma ligands appear to inhibit cytokine signaling in beta-cells is by the induction of endoplasmic reticulum (ER) stress or the unfolded protein response (UPR). Evidence is presented demonstrating that PPAR-gamma ligands activate the UPR and that activation of this cellular response pathway renders beta-cells inert to cytokine signaling.