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Reply to Gurgul-Convey and Lenzen: Cytokines, Nitric Oxide, and β-Cells

Open AccessPublished:April 17, 2015DOI:https://doi.org/10.1074/jbc.L115.648600
      This is a response to a letter by Gurgul-Convey and Lenzen (
      • Gurgul-Convey E.
      • Lenzen S.
      Is nitric oxide really the primary mediator of pancreatic β-cell death in type 1 diabetes?.
      )
      Drs. Gurgul-Convey and Lenzen (
      • Gurgul-Convey E.
      • Lenzen S.
      Is nitric oxide really the primary mediator of pancreatic β-cell death in type 1 diabetes?.
      ) contend that IL-1 alone inhibits β-cell function but the addition of TNFα is required to cause β-cell death. This is a selective view of the literature. IL-1 alone kills rat islet cells, independent of TNFα, whereas human and mouse islets require a combination of IL-1 and IFNγ. TNFα is dispensable for β-cell death in vitro (
      • Mandrup-Poulsen T.
      The role of interleukin-1 in the pathogenesis of IDDM.
      ). Further, they propose that TNFα causes β-cell death in type 1 diabetes (T1D) because it is present in inflamed islets from rodents and humans with T1D (
      • Jörns A.
      • Arndt T.
      • Meyer zu Vilsendorf A.
      • Klempnauer J.
      • Wedekind D.
      • Hedrich H.J.
      • Marselli L.
      • Marchetti P.
      • Harada N.
      • Nakaya Y.
      • Wang G.S.
      • Scott F.W.
      • Gysemans C.
      • Mathieu C.
      • Lenzen S.
      Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
      ). We argue that the presence of TNFα in insulitic lesions does not implicate this molecule as causative of β-cell death. Moreover, TNFR1 is not required for β-cell destruction in the nonobese diabetic (NOD) mouse (
      • Chee J.
      • Angstetra E.
      • Mariana L.
      • Graham K.L.
      • Carrington E.M.
      • Bluethmann H.
      • Santamaria P.
      • Allison J.
      • Kay T.W.
      • Krishnamurthy B.
      • Thomas H.E.
      TNF receptor 1 deficiency increases regulatory T cell function in nonobese diabetic mice.
      ).
      It is suggested that the absence of peroxynitrite formation in cytokine-treated β-cells is due to the dismutation of superoxide by manganese superoxide dismutase (Mn-SOD), leaving H2O2 to react with NO-forming hydroxyl radical. Why would NO be necessary when iron and H2O2 generate hydroxyl radical by the Fenton reaction? Further, NO inhibits this reaction (
      • Lu C.
      • Koppenol W.H.
      Inhibition of the Fenton reaction by nitrogen monoxide.
      ). A vast body of literature supports the idea that NO is freely diffusible and reacts at diffusion-controlled rates with superoxide to form peroxynitrite, allowing NO to effectively compete with Mn-SOD for mitochondrially generated superoxide. Consistent with many studies, peroxynitrite is formed when NO and superoxide are generated (
      • Broniowska K.A.
      • Mathews C.E.
      • Corbett J.A.
      Do β-cells generate peroxynitrite in response to cytokine treatment?.
      ). We report that NO is the primary mediator of cytokine-induced damage, as β-cells fail to produce superoxide in response to cytokines. When chemically produced, superoxide scavenges nitric oxide (forming peroxynitrite) and protects against NO-mediated damage (
      • Broniowska K.A.
      • Mathews C.E.
      • Corbett J.A.
      Do β-cells generate peroxynitrite in response to cytokine treatment?.
      ).

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        • Lenzen S.
        Is nitric oxide really the primary mediator of pancreatic β-cell death in type 1 diabetes?.
        J. Biol. Chem. 2015; 290: 10570
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        The role of interleukin-1 in the pathogenesis of IDDM.
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        • Arndt T.
        • Meyer zu Vilsendorf A.
        • Klempnauer J.
        • Wedekind D.
        • Hedrich H.J.
        • Marselli L.
        • Marchetti P.
        • Harada N.
        • Nakaya Y.
        • Wang G.S.
        • Scott F.W.
        • Gysemans C.
        • Mathieu C.
        • Lenzen S.
        Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes.
        Diabetologia. 2014; 57: 512-521
        • Chee J.
        • Angstetra E.
        • Mariana L.
        • Graham K.L.
        • Carrington E.M.
        • Bluethmann H.
        • Santamaria P.
        • Allison J.
        • Kay T.W.
        • Krishnamurthy B.
        • Thomas H.E.
        TNF receptor 1 deficiency increases regulatory T cell function in nonobese diabetic mice.
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        • Lu C.
        • Koppenol W.H.
        Inhibition of the Fenton reaction by nitrogen monoxide.
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        • Mathews C.E.
        • Corbett J.A.
        Do β-cells generate peroxynitrite in response to cytokine treatment?.
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