Immunosuppressive and anti-inflammatory action of antioxidants in rat autoimmune diabetes.
Oxidative stress makes an important contribution to the development of autoimmune diabetes. We therefore tested the possible therapeutic value of two anti-oxidants, butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC), in the animal model of diabetes induced in susceptible DA rats by multiple low doses of streptozotocin (MLD-SZ, 20 mg/kg/day for 5 days). Administration of either BHA, or PDTC (50 mg/kg/day for 7 days), after finishing MLD-SZ injections, attenuated both the development of hyperglycemia and insulitis. Ex vivo analysis revealed that BHA treatment reduced the proliferation of autoreactive lymphocytes and down-regulated their adhesion to endothelium. In addition, BHA markedly attenuated the production of proinflammatory cytokines IL-1beta and TNF-alpha by both islets of pancreas and peritoneal macrophages. In parallel, macrophage release of cytotoxic oxygen and nitrogen intermediates superoxide anion (O(2)*(-)) and nitric oxide (NO*), respectively, was significantly inhibited. Finally, BHA treatment reduced intrapancreatic expression of inducible NO synthase (iNOS) and consequent production of NO* by pancreatic islets. Together, these data indicate that antioxidant agents might be a feasible therapeutic tools to interfere with development of autoimmune diabetes at multiple levels, including lymphocyte proliferation and adhesion, as well as the production of proinflammatory and cytotoxic mediators.
Stosic-Grujicic
Stanislava D
SD
Laboratory of Immunology, Institute for Biological Research Sinisa Stankovic, 29 Novembra 142, 11000 Belgrade, Yugoslavia. duta@eunet.yu
Miljkovic
Djordje M
DM
Cvetkovic
Ivana D
ID
Maksimovic-Ivanic
Danijela D
DD
Trajkovic
Vladimir
V
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use*; D015551:Autoimmunity / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011759:Pyrrolidines / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D002083:Butylated Hydroxyanisole; C020972:pyrrolidine dithiocarbamic acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat