title: Beta-cell specific production of IL6 in conjunction with a mainly intracellular but not mainly surface viral protein causes diabetes.
abstract: Inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. IL6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. The aim of this study was to investigate how beta-cell specific overexpression of IL-6 influences diabetes development. We developed two lines of rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) mice that also co-express IL6 in their beta-cells. Expression of the viral nucleoprotein (NP), which has a predominantly intracellular localization, together with IL6 led to hyperglycemia, which was associated with a loss of GLUT-2 expression in the pancreatic beta-cells and infiltration of CD11b(+) cells, but not T cells, in the pancreas. In contrast, overexpression of the LCMV glycoprotein (GP), which can localize to the surface, with IL-6 did not lead to spontaneous diabetes, but accelerated virus-induced diabetes by increasing autoantigen-specific CD8(+) T cell responses and reducing the regulatory T cell fraction, leading to increased pancreatic infiltration by CD4(+) and CD8(+) T cells as well as CD11b(+) and CD11c(+) cells. The production of IL-6 in beta-cells acts prodiabetic, underscoring the potential benefit of targeting IL6 in diabetes.
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. Electronic address: tom.vanbelle@med.kuleuven.be.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Van Belle
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Pagni
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Liao
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Sowbarnika
authors.initials: S
authors.lastname: Sachithanantham
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Dave
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Amira
authors.initials: A
authors.lastname: Bel Hani
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Manenkova
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Amirian
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Bret
authors.initials: B
authors.lastname: Morin
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The School of Molecular Bioscience, University of Sydney, NSW 2006, Australia.
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. Electronic address: matthias@liai.org.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000276:immunology; D006943:Hyperglycemia / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology*; D051381:Rats
chemical_list: D051273:Glucose Transporter Type 2; D015850:Interleukin-6; D009698:Nucleoproteins; C495682:Slc2a2 protein, mouse
keywords: Cytokine; GLUT-2; Inflammation; T cell; Type 1 diabetes