INTERLEUKIN 1β-MEDIATED INHIBITION OF ARGINASE IN RINm5F CELLS

Cunningham, James M.; Mabley, Jon G.; Green, I C

doi:10.1006/cyto.1996.0203

Cited by 17 publications

(16 citation statements)

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“…We now need to identify these "prosurvival" or "proapoptosis" patterns of gene and protein expression by DNA microarray and proteomic analysis, respectively, and next, elucidate the nature of the transcription factors regulating these "gene modules." The transcription factor NF-B, for instance, seems to play a central role in the regulation of several cytokine-induced genes in ␤-cells (24,52,53), including the "NO-formation module" consisting of upregulated iNOS and AS (24) and, possibly, downregulated arginase (54). The identification of these modules and their controlling transcription factorsa formidable task-would permit interventions aimed at blocking cytokine-induced deleterious ␤-cell genes while preserving induction of defense/repair genes.…”

Section: Rat/mouse ␤-Cellsmentioning

confidence: 99%

beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

Eizirik

Darville²

2001

Diabetes

160

109

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Increased evidence suggests that apoptosis is the main mode of ␤-cell death in early type 1 diabetes. Cytokines mediate ␤-cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may contribute to ␤-cell survival or death. The gene encoding for the inducible form of nitric oxide synthase is induced by interleukin (IL)-1␤ or IL-1␤ plus ␥-interferon in rodent and human islets, respectively. This leads to nitric oxide (NO) formation, which contributes to a major extent to ␤-cell necrosis and to a minor extent to the process of ␤-cell apoptosis. The main mode of cell death induced by cytokines in human ␤-cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse ␤-cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and consequent decreased ATP production. Human islets, possessing better antioxidant defenses, are able to preserve glucose oxidation and ATP production, and can thus complete the apoptotic program after the death signal delivered by cytokines. We propose that this death signal results from cytokine-induced parallel and/or sequential changes in the expression of multiple proapoptotic and prosurvival genes. The identity of these "gene modules" and of the transcription factors regulating them remains to be established. Diabetes 50 (Suppl. 1):S64-S69, 2001 H yperglycemia in type 1 diabetes probably results from a long-term negative balance between immune-mediated ␤-cell damage (1) and ␤-cell repair/regeneration (2). Once macrophages and T-cells have been attracted to the islets and activated, they secrete soluble mediators such as cytokines, oxygen free radicals, and nitric oxide (NO), which probably contribute to ␤-cell dysfunction and death (3-5). Under in vitro conditions, interleukin (IL)-1␤, in combination with interferon (IFN)-␥ and/or tumor necrosis factor (TNF)-␣, induces severe functional suppression and death by apoptosis in rodent pancreatic islet cells (3,6,7). Human islets are less sensitive to the deleterious effects of cytokines, but their exposure for several days to IL-1␤ plus TNF-␣ plus IFN-␥ induces ␤-cell functional impairment and death by apoptosis (4,8). Interestingly, neither IL-1␤ nor IFN-␥ alone induces apoptosis in human ␤-cells, whereas the combination of these cytokines directly induces ␤-cell death (8,9). A potential indirect effect of cytokines is upregulation of the ␤-cell Fas receptor, increasing the susceptibility of these cells to apoptosis mediated by Fas ligand (FasL), expressed on the surface of invading T-cells and macrophages (10)(11)(12). Recent data indicate that Fas expression and apoptosis are also present in human ␤-cells in the early stages of type 1 diabetes (11,13).Apoptosis is apparently the main mode of ␤-cell death in NOD mice (14). In this species, ␤-cell apoptosis precedes massive T-cell infiltration (15), reinforcing a putative role for inflammatory mediators produced by early infiltrating cells such as macrophages and dendritic cel...

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Section: Rat/mouse ␤-Cellsmentioning

confidence: 99%

beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

Eizirik

Darville²

2001

Diabetes

160

109

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“…L-Arginase activity may be increased in peritoneal macrophages after exposure to LPS (Currie, 1978), while wound and peritoneal macrophages convert L-arginine to L-citrulline and L-ornithine at comparable rates, indicating that both iNOS and L-arginase pathways are functional (Granger et al, 1990). In clonal -cells, IL-1 increases L-arginase activity with concomitant increase in NO production (Cunningham et al, 1997), which suggests a kind of coordinated regulation of L-arginase and iNOS in these cells. There is also evidence for a reciprocal regulation of NOS and L-arginase during immune responses via the antagonistic effects of cytokines released from Th1 and Th2 lymphocytes.…”

Section: Participation Of L-arginine/l-glutamine Coupling In Diabetesmentioning

confidence: 95%

“…This fact may be of relevance for -cells during Th1-driven insulitis, since L-arginine concentrations are likely to be reduced at sites of inflammation due to the release of soluble L-arginase from infiltrating macrophages (Albina et al, 1990). Corroborating this proposition is the fact that IL-1-induction of NO synthesis in RINm5F insulin secreting -like cells is accompanied by a reduced flux of L-arginine through L-arginase, an effect that appears to be mediated by L-NOHA (Cunningham et al, 1997). Hence, it is likely that, following immune cell-elicited NO production via iNOS, L-NOHA inhibits islet L-arginase activity to some degree in vivo, which may be strongly exacerbated by the pro-inflammatory cytokine IL-1 that inhibits L-arginase expression in -cells Rieneck et al, 2000).…”

Section: Participation Of L-arginine/l-glutamine Coupling In Diabetesmentioning

confidence: 97%

“…In addition to this, pancreatic -cells express another L-arginine-metabolising enzyme, i.e. L-arginase (L-arginine amidinohydrolase, EC 3.5.3.1), which allows for the completion of urea production through the formation of L-ornithine and urea from L-arginine (Cunningham et al, 1997). Physiologic levels of L-arginase gene expression and activity have been measured in rat -cells and the insulin-secreting cell line RINm5F (Cunningham et al, 1997;Malaisse et al, 1989;Cardozo et al, 2001;Rieneck et el., 2000).…”

Section: Participation Of L-arginine/l-glutamine Coupling In Diabetesmentioning

confidence: 99%

“…Indeed, substantial amounts of this metabolite are released by LPS-treated rat alveolar macrophages , while inhibition of L-arginase by L-NOHA may ensure sufficient availability of L-arginine for high-output production of NO in activated cells. L-Citrulline, the co-product of iNOS catalysis, and S-nitrosoglutathione (SNOG), an adduct produced by the reaction of NO with GSH, are also inhibitors of L-arginase in many cell types (Daghigh et al, 1994;Knowles & Moncada, 1994), including -cells (Cunningham et al, 1997). Hence, intermediates of NO synthesis, as well as NO itself, precisely coordinate a maximum of flux through iNOS in insulin-producing pancreatic cells (Fig.…”

Section: Participation Of L-arginine/l-glutamine Coupling In Diabetesmentioning

confidence: 99%

See 2 more Smart Citations

A Novel L-Arginine/L-Glutamine Coupling Hypothesis: Implications for Type 1 Diabetes

Bittencourt¹,

Newsholme²

2011

Type 1 Diabetes - Complications, Pathogenesis, and Alternative Treatments

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Type 1 diabetes: can exercise impair the autoimmune event? TheL‐arginine/glutamine coupling hypothesis

Krause

Bittencourt

2008

Cell Biochemistry & Function

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Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against beta-cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T-helper lymphocyte of type 1 (Th1) subset of T-lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL-2), interferon gamma (IFN-gamma) and tumour necrosis factor beta (TNF-beta)] prevail over immunoregulatory (anti-inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL-4, IL-6 and IL-10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Activation of sympathetic-corticotropin-releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L-arginine supply for nitric oxide (NO)-assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L-arginine, leading to a redox imbalance that activates nuclear factor kappaB exacerbating inflammation and NO-mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70-kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise-induced anti-inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against beta-cells and how novel therapeutic approaches may be inferred from these observations.

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INTERLEUKIN 1β-MEDIATED INHIBITION OF ARGINASE IN RINm5F CELLS

Cited by 17 publications

References 0 publications

beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes.

A Novel L-Arginine/L-Glutamine Coupling Hypothesis: Implications for Type 1 Diabetes

Type 1 diabetes: can exercise impair the autoimmune event? TheL‐arginine/glutamine coupling hypothesis

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