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α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation

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Abstract

Although islet transplantation for individuals with type 1 diabetes has been shown to yield superior blood glucose control, it remains inadequate for long-term control. This is partly due to islet injuries and stresses that can lead to beta cell loss. Inhibition of excess IL-1β activity might minimize islet injuries, thus preserving function. The IL-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1β, protects islets from cytokine-induced necrosis and apoptosis. Therefore, an imbalance between IL-1β and IL-1Ra might influence the courses of allogeneic and autoimmune responses to islets. Our group previously demonstrated that the circulating serine-protease inhibitor human alpha-1-antitrypsin (hAAT), the levels of which increase in circulation during acute-phase immune responses, exhibits anti-inflammatory and islet-protective properties, as well as immunomodulatory activity. In the present study, we sought to determine whether the pancreatic islet allograft-protective activity of hAAT was mediated by IL-1Ra induction. Our results demonstrated that hAAT led to a 2.04-fold increase in IL-1Ra expression in stimulated macrophages and that hAAT-pre-treated islet grafts exhibited a 4.851-fold increase in IL-1Ra transcript levels, which were associated with a moderate inflammatory profile. Unexpectedly, islets that were isolated from IL-1Ra-knockout mice and pre-treated with hAAT before grafting into wild-type mice yielded an increase in intragraft IL-1Ra expression that was presumably derived from infiltrating host cells, albeit in the absence of hAAT treatment of the host. Indeed, hAAT-pre-treated islets generated hAAT-free conditioned medium that could induce IL-1Ra production in cultured macrophages. Finally, we demonstrated that hAAT promoted a distinct phosphorylation and nuclear translocation pattern for p65, a key transcription factor required for IL-1Ra expression.

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  1. Avishag Abecassis and Ronen Schuster: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel

    Avishag Abecassis, Ronen Schuster, Galit Shahaf, Eyal Ozeri, Ross Green, David E Ochayon, Peleg Rider & Eli C Lewis

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  1. Avishag Abecassis
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  2. Ronen Schuster
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Abecassis, A., Schuster, R., Shahaf, G. et al. α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation. Cell Mol Immunol 11, 377–386 (2014). https://doi.org/10.1038/cmi.2014.17

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