Increased blood flow and vascular leakage of proteins preferentially affect tissues that are sites of diabetic complications in humans and animals. These vascular changes in diabetic rats are largely prevented by aminoguanidine. Glucose-induced vascular changes in nondiabetic rats are also prevented by aminoguanidine and by A^-monomethyl-L-arginine (NMMA), an established inhibitor of nitric oxide (NO) formation from L-arginine. Aminoguanidine and NMMA are equipotent inhibitors of interleukin-1 p-induced 1) nitrite formation (an oxidation product of NO) and cGMP accumulation by the rat p-cell insulinoma cell line RINm5F, and 2) inhibition of glucose-stimulated insulin secretion and formation of iron-nitrosyl complexes by islets of Langerhans. In contrast, NMMA is ~40 times more potent than aminoguanidine in elevating blood pressure in nondiabetic rats. These results demonstrate that aminoguanidine inhibits NO production and suggest a role for NO in the pathogenesis of diabetic vascular complications. Diabetes 41:552-56, 1992 N itric oxide synthase catalyzes the mixed functional oxidation of a guanidino nitrogen atom of L-arginine to yield L-citrulline and NO-(1,2). The constitutive isoform of NO-synthase is Ca 2+ dependent and produces small amounts of NO-that activate guanylate cyclase, resulting in the formation of cGMP, which mediates endothelium-dependent relaxation (2) and neural transmission (3). NO-is produced in much larger amounts by the cytokine-and endotoxininducible isoform of NO-synthase, which is Ca 2+ inde-

Schwann cell dedifferentiation and proliferation is a prerequisite to axonal regeneration in the injured peripheral nervous system. The neuregulin (NRG) family of growth and differentiation factors may play a particularly important role in this process, because these axon-associated molecules are potent Schwann cell mitogens and differentiation factors in vitro. We have examined Schwann cell DNA synthesis and the expression of NRGs and their receptors, the erbB membrane tyrosine kinases, in rat sciatic nerve, sensory ganglia, and spinal cord 0 -30 d postaxotomy. Analysis of NRG cDNAs from these tissues revealed several novel splice variants and showed that cells endogenous to injured nerve express NRG mRNAs. A selective induction of mRNAs encoding the glial growth factor (GGF) subfamily of NRGs occurs in nerve beginning 3 d postaxotomy and thus coincides with the onset of Schwann cell DNA synthesis. In later stages of Wallerian degeneration, however, Schwann cell mitogenesis markedly decreases, whereas elevated GGF expression persists. Of the four known erbB kinases, Schwann cells express both erbB2 and erbB3 receptors over the entire interval studied. Expression of erbB2 and erbB3 is coordinately induced in response to axotomy, indicating that Schwann cell responses to NRGs may be modulated by changes in receptor density. Neuregulin (including transmembrane precursors) and erbB protein are associated with Schwann cells postaxotomy. Thus, in contrast to the concept of NRGs as axon-associated mitogens, our findings suggest that NRGs produced by Schwann cells themselves may be partially responsible for Schwann cell proliferation during Wallerian degeneration, probably acting via autocrine or paracrine mechanisms.

SUMMARY Immune cells sense microbial products through Toll-like receptors (TLR), which trigger host defense responses including type 1 interferons (IFNs) secretion. A coding polymorphism in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is a susceptibility allele for human autoimmune and infectious disease. We report that Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses and was critical for TLR agonist-induced, type 1 IFN-dependent suppression of inflammation in colitis and arthritis. PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination. The disease-associated PTPN22W variant failed to promote TRAF3 ubiquitination, type 1 IFN upregulation, and type 1 IFN-dependent suppression of arthritis. The findings establish a candidate innate immune mechanism of action for a human autoimmunity “risk” gene in the regulation of host defense and inflammation.

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A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased insulin secretion and diabetes. To test this critical prediction, we generated transgenic mice expressing beta cell K(ATP) channels with reduced ATP sensitivity. Animals develop severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days and typically die within 5. Nevertheless, islet morphology, insulin localization, and alpha and beta cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicate that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion.

Cytokines have been implicated s immunological effector molecules that mediate beta cell destruction asciated with insulin-dependent diabetes mellitus. In this report we demonstrate that the cytokine combination of human recombinant interieukin lp (IL-1*), tumor necrosis factor a (TNF-a), and interferon y (IFN-y) induces the formation of nitric oxide by human islets. This combination of cytokines stimulates both the formation of the nitric oxide derivative, nitrite, and the accumulation of cGMP by human iWets. The nitric oide synthase inhibitor NG.monomethyl-L-argIne prevents formation of both cGMP and nitrite. IL-1,B and IFN-y are sufcient to induce nitric oide formation by human islets, whereas TNF-a potentiates nitrite production. This combination of cytokines (IL-1f3, TNF-a, and IFN-y) also influences insulin secretion by human idets. Pretreatment of human iWets with low concentrations of this cytokne combination (IL-lp at 15 units/ml, 0.7 nM TNF-a, and IFN-y at 150 units/ml) appears to slightly stimulate insulin secretion. Higher concentrations (IL-l1 at 75 units/nl, 3.5 nM TNF-a, and IFN-yat 750 units/ml) inhibit inlin secretion from human islets, and the inhibitory effect is prevented by NG-monomethyl-L-argine. This higher concentration of cytokines also induces the formation of an electron paramagnetic resonance-detectable g = 2.04 axial feature by human islets that is characteristic of the formation of an iron-diho-dinitrosyl complex. The formation of this complex is prevented by NG-monomethyl-L-arginine, thus confirming that this cytokine combination induces the formation of nitric oxide by human islets. These results indicate that nitric oxide mediates the inhibitory effects of cytoldnes on glucosestimulated insulin secretion by human Wets and suggest that nitric oidde may participate in beta-cell dysfunction associated with insulin-dependent diabetes mellitus.Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by specific destruction of the pancreatic islet beta cell (1). The destruction of beta cells is believed to be mediated by infiltrating lymphocytes. The ability of T cells to adoptively transfer diabetes in diabetesprone BB rats (2) and in the NOD mouse indicates that T cells participate in beta-cell destruction (3). Cytokines, released by infiltrating lymphocytes, have also been implicated as possible mediators of beta-cell destruction. Pretreatment of isolated rat islets with the cytokine human recombinant interleukin 1,B (IL-1*8) results in a concentration-and timedependent inhibition of glucose-stimulated insulin secretion that is followed by islet destruction after prolonged exposures to this cytokine (4, 5).The free-radical nitric oxide has been implicated as the cellular effector molecule that mediates the inhibitory and cytotoxic effects of IL-1,3 on rat islets (6). Pretreatment of rat islets for 18-24 hr with IL-1lB results in nearly complete inhibition of glucose-stimulated insulin secretion that is prevented by the nitric oxide synthase inhibitor...

Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease characterized by the destruction of insulin-secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β-cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4+ and CD8+ T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β-cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β-cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox-dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β-cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL-1 and IFN-γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.

IntroductionNitric oxide has recently been implicated as the effector molecule that mediates IL-1(3-induced inhibition of glucose-stimulated insulin secretion and (3-cell specific destruction. The pancreatic islet represents a heterogeneous cell population con-