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Interleukin-17 stimulates inducible nitric oxide synthase-dependent toxicity in mouse beta cells

D Miljkovic1, I Cvetkovic, M Momcilovic

  • 1Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia and Montenegro.

Cellular and Molecular Life Sciences : CMLS
|November 2, 2005
PubMed

Insights

Interleukin-17 (IL-17) amplifies nitric oxide (NO) production by inducing the expression of inducible NO synthase (iNOS) in pancreatic cells. This IL-17 mediated NO release contributes to beta cell damage, potentially playing a role in diabetes.

Area of Science:

  • Immunology
  • Endocrinology
  • Molecular Biology

Background:

  • Proinflammatory cytokines, including IL-17, are implicated in autoimmune diseases.
  • Nitric oxide (NO) synthase (iNOS) plays a role in inflammatory responses.
  • The precise role of IL-17 in iNOS-mediated NO production in pancreatic beta cells requires further elucidation.

Purpose of the Study:

  • To investigate the influence of IL-17 on iNOS-mediated NO release in pancreatic beta cells.
  • To explore the signaling pathways involved in IL-17-induced NO production.
  • To assess the contribution of IL-17 to beta cell damage in a model of diabetes.

Main Methods:

  • Experiments were conducted using the mouse insulinoma cell line MIN6 and primary mouse pancreatic islets.
  • Cells were treated with combinations of interferon-gamma, tumor necrosis factor-alpha, and IL-1beta, with or without IL-17.
  • iNOS expression and NO production were measured.
  • p38 mitogen-activated protein kinase (MAPK) phosphorylation was assessed.
  • A multiple low-dose streptozotocin model of diabetes was used to measure blood IL-17 levels.

Main Results:

  • IL-17 significantly augmented iNOS mRNA/protein expression and NO production induced by other proinflammatory cytokines.
  • IL-17-induced iNOS expression was dependent on p38 MAPK activation.
  • IL-17 enhanced the NO-dependent toxicity of proinflammatory cytokines towards MIN6 cells.
  • Neutralizing antibodies against IL-17 reduced NO production and protected cells from damage.
  • Elevated blood IL-17 levels were observed in a mouse model of diabetes.

Conclusions:

  • IL-17 promotes iNOS expression and NO release in pancreatic beta cells via p38 MAPK signaling.
  • IL-17 contributes to NO-dependent beta cell damage.
  • T cell-derived IL-17 may be involved in beta cell destruction in diabetes.

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