Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA–seq) to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ). Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the immune system and beta cell level.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease with a strong genetic component [1]
Pancreatic beta cells are destroyed by the immune system in type 1 diabetes mellitus, causing insulin dependence for life
Candidate genes for diabetes contribute to this process by acting both at the immune system and, as we suggest here, at the pancreatic beta cell level
Summary
Type 1 diabetes (T1D) is an autoimmune disease with a strong genetic component [1]. We have previously proposed that insulitis, the pancreatic islet inflammation present in T1D, results from a ‘‘dialog’’ between immune cells homing into the islets and the target beta cells. Beta cells contribute to this dialog by local release of cytokines and chemokines and by delivering immunogenic signals during the cell death process; this, together with signals generated by invading immune cells, contributes to trigger and amplify (or dampen) insulitis [2]. The amplification or resolution of insulitis, and its progression or not to disease, probably depends on an interplay between environmental triggers, such as dietary components or viral infections, and the patient’s genetic background [2,3,4] acting at least in part at the pancreatic beta cell level [5,6,7]. It is important to identify the molecular mechanisms by which immune signals and genetic and/or environmental factors affect beta cell survival and the production of inflammatory mediators such as chemokines and cytokines
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