title: α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation.
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.
authors.forename: Avishag
authors.initials: A
authors.lastname: Abecassis
authors.forename: Ronen
authors.initials: R
authors.lastname: Schuster
authors.forename: Galit
authors.initials: G
authors.lastname: Shahaf
authors.forename: Eyal
authors.initials: E
authors.lastname: Ozeri
authors.forename: Ross
authors.initials: R
authors.lastname: Green
authors.forename: David E
authors.initials: DE
authors.lastname: Ochayon
authors.forename: Peleg
authors.initials: P
authors.lastname: Rider
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D011183:Postoperative Complications / Q000517:prevention & control*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage*
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C498144:Rela protein, mouse; C043392:SERPINA1 protein, human; D051996:Transcription Factor RelA; D000515:alpha 1-Antitrypsin