Activation of peroxisome proliferator-activated receptor-γ protects pancreatic β-cells from cytokine-induced cytotoxicity via NFκB pathway

Abstract

Diabetes mellitus is characterized by cytokine-induced insulitis and a deficit in β-cell mass. Ligands for peroxisome proliferator-activated receptor-γ (PPAR-γ) have been shown to have anti-inflammatory effects in various experimental models. We questioned whether activation of endogenous PPAR-γ by either PPAR-γ ligands or adenoviral-directed overexpression of PPAR-γ (Ad-PPAR-γ) could inhibit cytokine-induced β-cell death in RINm5F (RIN) cells, a rat insulinoma cell line. Treatment of RIN cells with interleukin-1β (IL-1β) and interferon-γ (IFN-γ) induced β-cell damage through NFκB-dependent signaling pathways. Activation of PPAR-γ by PPAR-γ ligands or Ad-PPAR-γ inhibited IL-1β and IFN-γ-stimulated nuclear translocation of the p65 subunit and DNA binding activity. NFκB target gene expression and their product formation, namely inducible nitric oxide synthase and cyclooxygenase-2 were decreased by PPAR-γ activation, as established by real-time PCR, Western blots and measurements of NO and PGE 2. The mechanism by which PPAR-γ activation inhibited NFκB-dependent cell death signals appeared to involve the inhibition of IκBα degradation, evidenced by inhibition of cytokine-induced NFκB-dependent signaling events by Ad-IκBα (S32A, S36A), non-degradable IκBα mutant. IκBβ mutant, Ad-IκBβ (S19A, S23A) was not effective in preventing cytokine toxicity. Furthermore, a protective effect of PPAR-γ ligands was proved by assaying for normal insulin secreting capacity in response to glucose in isolated rat pancreatic islets. The β-cell protective function of PPAR-γ ligands might serve to counteract cytokine-induced β-cell destruction.