title: Deletion of 12/15-lipoxygenase alters macrophage and islet function in NOD-Alox15(null) mice, leading to protection against type 1 diabetes development.
abstract: OBJECTIVE
  Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D.
  
  
  METHODS
  12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass.
  
  
  RESULTS
  12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass.
  
  
  CONCLUSIONS
  These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.
authors: Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA.
authors: Shamina M
authors: SM
authors: Green-Mitchell
authors: Sarah A
authors: SA
authors: Tersey
authors: Banumathi K
authors: BK
authors: Cole
authors: Kaiwen
authors: K
authors: Ma
authors: Norine S
authors: NS
authors: Kuhn
authors: Tina Duong
authors: TD
authors: Cunningham
authors: Nelly A
authors: NA
authors: Maybee
authors: Swarup K
authors: SK
authors: Chakrabarti
authors: Marcia
authors: M
authors: McDuffie
authors: David A
authors: DA
authors: Taylor-Fishwick
authors: Raghavendra G
authors: RG
authors: Mirmira
authors: Jerry L
authors: JL
authors: Nadler
authors: Margaret A
authors: MA
authors: Morris
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics; D010105:Oxygenases / Q000235:genetics*
chemical_list: C475064:12-15-lipoxygenase; D007328:Insulin; D018664:Interleukin-12; D010105:Oxygenases; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; C114415:nitric oxide dioxygenase