title: Anti-diabetic actions of carbon monoxide-releasing molecule (CORM)-A1: Immunomodulation and regeneration of islet beta cells.
abstract: We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as well as beta cell regeneration. CORM-A1 (2 mg/kg/day) was administered for 10 days to mice induced with MLDS and/or depleted of low dose cyclophosphamide (CY)-sensitive FoxP3+ T regulatory (Treg) cells. Besides monitoring hyperglycaemia, ex vivo analysis of spleen, pancreatic lymph nodes (PLN) and pancreas was performed at the end of treatment. In CORM-A1-treated MLDS-induced mice the improvement of hyperglycaemia was observed only without depletion of CY-sensitive FoxP3+ Treg cells. This was accompanied by decreased levels of interleukin (IL)-12, IL-2 and early activation marker CD25 in the spleen and PLN and increased transforming growth factor (TGF)-β, resulting in reduced lymphocyte proliferation in both organs. In parallel, decreased transcript levels of IL-2, but increased mRNA expression of TGF-β, accompanied with up-regulation of Ki-67 protein expression was observed within pancreas. Together, the data suggested that besides the immunomodulatory potential, CORM-A1 probably induces beta cell regeneration.
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikolic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Saksida
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Vujicic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Stojanovic
authors.affiliation: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia. Electronic address: duta@eunet.rs.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stosic-Grujicic
mesh_terms: D000818:Animals; D001880:Boranes / Q000008:administration & dosage / Q000494:pharmacology*; D002254:Carbonates / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology; D056747:Immunomodulation / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D001880:Boranes; D002254:Carbonates; D016207:Cytokines; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; C503854:sodium boranocarbonate
keywords: Carbon monoxide-releasing molecule A1; Cytokines; Islets of Langerhans; Lymphocytes; Type 1 diabetes