Abstract
Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease arising from a targeted immune-mediated destruction of the insulin-producing β cells resided in the pancreatic islets of Langerhans
To investigate if the cathepsin proteases in general are expressed and regulated by pro-inflammatory cytokines, we examined the expression of the 15 human cathepsins by real-time qPCR in isolated human pancreatic islets left untreated or exposed to IL-1β+IFN-γ for 24 h
Six cathepsins were differentially expressed in human islets exposed to IL-1β+IFN-γ; cathepsin C (CTSC), O (CTSO) and S (CTSS) were upregulated, whereas cathepsin D (CTSD), F (CTSF) and cathepsin H (CTSH) were downregulated (BH-corrected p < 0.05; Figure 1a)
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease arising from a targeted immune-mediated destruction of the insulin-producing β cells resided in the pancreatic islets of Langerhans. We previously reported that CTSH is downregulated by pro-inflammatory cytokines in human islets as well as in rat and human β cells, and that cathepsin H regulates β-cell function, apoptosis and disease progression in children with newly diagnosed T1D [15,19]. A recent study by Lambelet et al indicated that cytokines impair lysosome function leading to lysosome membrane permeabilization, cathepsin B leakage and β-cell death [5]. The cathepsin proteases have been implicated in β-cell dysfunction and death in response to known β-cell stressors in type 2 diabetes (T2D), i.e., high glucose and free fatty acids (FFA) [20,21]. Using different β-cell model systems, we examined the gene expression profile of the cathepsins in response to pro-inflammatory cytokines and investigated their role in cytokine-induced apoptosis. We demonstrate that cytokines modulate the expression of several cathepsins, and that cathepsin C participates in the regulation of cytokine-induced β-cell apoptosis
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