Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.

Autoimmune diseases are typically studied with a focus on the immune system, and less attention is paid to responses of target tissues exposed to the immune assault. We presently evaluated, based on available RNA sequencing data, whether inflammation induces similar molecular signatures at the target tissues in type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. We identified confluent signatures, many related to interferon signaling, indicating pathways that may be targeted for therapy, and observed a high (>80%) expression of candidate genes for the different diseases at the target tissue level. These observations suggest that future research on autoimmune diseases should focus on both the immune system and the target tissues, and on their dialog. Discovering similar disease-specific signatures may allow the identification of key pathways that could be targeted for therapy, including the repurposing of drugs already in clinical use for other diseases.

Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1ß-induced apoptosis via Bim/A1 imbalance.

We have recently shown that the crosstalk between mild endoplasmic reticulum (ER) stress and low concentrations of the pro-inflammatory cytokine interleukin (IL)-1ß exacerbates beta cell inflammatory responses via the IRE1α/XBP1 pathway. We presently investigated whether mild ER stress also sensitizes beta cells to cytokine-induced apoptosis. Cyclopiazonic acid (CPA)-induced ER stress enhanced the IL-1ß apoptosis in INS-1E and primary rat beta cells. This was not prevented by XBP1 knockdown (KD), indicating the dissociation between the pathways leading to inflammation and cell death. Analysis of the role of pro- and anti-apoptotic proteins in cytokine-induced apoptosis indicated a central role for the pro-apoptotic BH3 (Bcl-2 homology 3)-only protein Bim (Bcl-2-interacting mediator of cell death), which was counteracted by four anti-apoptotic Bcl-2 (B-cell lymphoma-2) proteins, namely Bcl-2, Bcl-XL, Mcl-1 and A1. CPA+IL-1ß-induced beta cell apoptosis was accompanied by increased expression of Bim, particularly the most pro-apoptotic variant, small isoform of Bim (BimS), and decreased expression of A1. Bim silencing protected against CPA+IL-1ß-induced apoptosis, whereas A1 KD aggravated cell death. Bim inhibition protected against cell death caused by A1 silencing under all conditions studied. In conclusion, mild ER stress predisposes beta cells to the pro-apoptotic effects of IL-1ß by disrupting the balance between pro- and anti-apoptotic Bcl-2 proteins. These findings link ER stress to exacerbated apoptosis during islet inflammation and provide potential mechanistic targets for beta cell protection, namely downregulation of Bim and upregulation of A1.

Differential usage of NF-κB activating signals by IL-1ß and TNF-α in pancreatic beta cells.

The cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)-α induce ß-cell death in type 1 diabetes via NF-κB activation. IL-1ß induces a more marked NF-κB activation than TNF-α, with higher expression of genes involved in ß-cell dysfunction and death. We show here a differential usage of the IKK complex by IL-1ß and TNF-α in ß-cells. While TNF-α uses IKK complexes containing both IKKα and IKKß, IL-1ß induces complexes with IKKα only; this effect is achieved by induction of IKKß degradation via the proteasome. Both IKKγ and activation of the TRAF6-TAK1-JNK pathway are involved in IL-1ß-induced IKKß degradation.