Expression and secretion of alpha1-proteinase inhibitor are regulated by proinflammatory cytokines in human pancreatic islet cells

Aims/hypothesis: Alpha1-proteinase inhibitor (alpha 1-PI) has been considered a key player in inflammatory processes. In humans, the main production site of alpha 1-PI is the liver, but other tissues, including pancreatic islets, also synthesise this molecule. The aims of this study were to assess the islet cell types that produce alpha 1-PI, to determine whether alpha 1-PI is actually secreted by islet cells, and to assess how its production and/or secretion are regulated. Methods: Expression of alpha 1-PI in human islet cells was assessed by immunofluorescence, electron microscopy and western blotting. Release of alpha 1-PI was analysed by reverse haemolytic plaque assay and ELISA. The effects of cytokines on alpha 1-PI synthesis and secretion were tested. Resulst: Immunofluorescence showed that alpha and delta cells do express alpha 1-PI, whereas beta cells do not. By electron microscopy, we demonstrated a colocalisation of alpha 1-PI with glucagon and somatostatin within secretory granules. Immunolabelling also revealed localisation of alpha 1-PI within the Golgi apparatus, related vesicles and lysosomal structures. The expression of alpha 1-PI in islet cells was also demonstrated by western blotting and ELISA of protein extracts. ELISA and reverse haemolytic plaque assay showed that alpha 1-PI is secreted into the culture medium. Treatment of islet cells with IL-1 beta and oncostatin M for 4 days increased the production and release of alpha 1-PI. Conclusion/interpretation: Our results demonstrate that alpha 1-PI is expressed by the alpha and delta cells of human islets, and that proinflammatory cytokines enhance the production and release of this inhibitor.