The specific p38 mitogen-activated protein kinase pathway inhibitor FR167653 keeps insulitis benign in nonobese diabetic mice

Ando, Hitoshi; Kurita, Seiichiro; Takamura, Toshinari

doi:10.1016/j.lfs.2003.09.045

Cited by 18 publications

(16 citation statements)

References 32 publications

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“…For example, several immunosuppressive agents halt T cell infiltration into the beta cells of the islets and prevent the develop- (Mori et al, 1986;Mahon et al, 1993;Casteels et al, 1998;Tabatabaie et al, 2000;Shapiro et al, 2002), but have no glucose-lowering effects in moderately or even mildly hyperglycemic NOD mice. Prophylactic treatment with the p38 MAPK inhibitor FR167653 has been shown to reduce pancreatic insulitis and reduce beta cell destruction in NOD mice (Ando et al, 2004). Although both FR167653 and SD-169 are specific p38 MAPK inhibitors, SD-169 is p38␣-selective, whereas FR167653 is not.…”

Section: Discussionmentioning

confidence: 99%

“…Although both FR167653 and SD-169 are specific p38 MAPK inhibitors, SD-169 is p38␣-selective, whereas FR167653 is not. Ando et al (2004) studied p38 pharmacology in a prophylactic mode but not in a therapeutic mode. In the present therapeutic modality study, SD-169 significantly lowered blood glucose levels not only in mildly (blood glucose levels around 150 mg/dl) but also moderately (blood glucose levels around 250 mg/dl) hyperglycemic NOD mice.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, progression from insulitis to diabetes in the NOD mouse is typically associated with Th1-mediated pancreatic inflammation (Cohen, 1997;Hill et al, 2003). Prophylactic treatment with the p38 MAPK inhibitor FR167653 has been shown to reduce pancreatic insulitis and reduce beta cell destruction in NOD mice, partly by inhibiting Th1-mediated immunity (Ando et al, 2004). The evidence suggests that p38 MAP kinase mediates several aspects of T cell function contributing to the destruction of pancreatic beta cells.…”

Section: Significant Reduction In Cd5mentioning

confidence: 99%

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Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Medicherla¹,

Protter²,

Jing³

et al. 2006

J Pharmacol Exp Ther

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Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38␣ MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immunohistochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5 ϩ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38␣-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38␣-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.Type 1 diabetes is a multifactorial disease in which autoimmunity plays a prime role. The disease becomes clinically manifest when the majority of endocrine beta cells have been destroyed in a T cell-mediated process (Yoshida and Kikutani, 2000). Methods that predict the development of type 1 diabetes may allow the evaluation of pharmacological treatment strategies that halt or even prevent beta cell destruction (Debussche et al., 1993;Keymeulen and Somer, 1993;Mahon et al., 1993;Ryu et al., 2001;Shapiro et al., 2002). Following the initiation of insulin therapy, 60 to 80% of patients with type 1 diabetes will experience a transient remission known as the honeymoon period (Keymeulen and Somer, 1993), and therapeutic strategies have been described to prolong this period by slowing the ongoing self-destruction of the insulin-producing beta cells (Hosker and Turner, 1982;Heinze and Thon, 1985;Crump, 1987;Palmer and McCulloch, 1990;Herold et al., 2002;Shapiro et al., 2002). Between 5 and 30% of adults presenting with mild hyperglycemia suggestive of type 2 diabetes may actually have a slowprogressive form of type 1 diabetes designated latent autoimmune diabetes of adults (Casteels et al., 1998). Immunosuppressive agents prevent the onset of type 1 diab...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significant Reduction In Cd5mentioning

confidence: 99%

See 1 more Smart Citation

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Medicherla¹,

Protter²,

Jing³

et al. 2006

J Pharmacol Exp Ther

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“…Levels of activated p38 are elevated in the skeletal muscle, adipose tissue and kidneys of diabetic patients [5][6][7], suggesting that some p38 responses may be important for the pathogenesis of diabetes and its complications. Functional blocking studies in animal models have demonstrated that p38 signalling induces the inflammation in insulitis and diabetic cardiomyopathy [8,9]. Furthermore, in vitro experiments have shown that p38 inhibition can suppress adipogenesis, prevent insulin resistance in myotubes exposed to TNF-α or oxidative stress and stimulate glucose transport in adipocytes [10,11]; however, these findings remain controversial.…”

Section: Introductionmentioning

confidence: 99%

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

et al. 2008

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Aims/hypothesis Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Methods Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Results Mkk3+/+ db/db and Mkk3 −/− db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 +/+ db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 −/− db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 −/− db/ db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 −/− db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. Conclusions/interpretation MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.

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“…Treating NOD mice with a p38 inhibitor reduced IFNγ production by spleen cells and reduced diabetes incidence without affecting islet infiltration [216]. This study suggests that the p38 pathway may be involved in the pathogenic pro-inflammatory cytokine production that leads to diabetes.…”

Section: Type I Diabetesmentioning

confidence: 68%

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

Zirnheld

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We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human Type Idiabetes. This protein is expressed at high levels throughout the lifespan of the mouse and correlates with increased pro-inflammatory cytokine production by the BMDC and IFNγ induction by T cells cocultured with the BMDC. These defects, including a similar pattern of pro-inflammatory cytokine production, are also observed in human monocytederived DC from diabetic patients. After exploring several potential mechanisms involved in the accumulation of β-catenin in NOD BMDC, we found that β-catenin is phosphorylated at higher levels in NOD BMDC at two residues associated with increased stabilization of this protein. Upon inhibition of the two kinases responsible for these phosphorylations, Akt and PKA, β-catenin expression is reduced. Therefore, β-catenin accumulates in NOD BMDC through an Akt and PKA-mediated mechanism. We also explored mechanisms by which β-catenin influences pro-inflammatory cytokine production and found that inhibition of β-catenin leads to decreased activation of the transcription factor NFκB, suggesting that pro-inflammatory cytokine production is increased in NOD BMDC through an NFκB-dependent mechanism. Finally, we v performed several in vivo experiments aimed at inhibiting β-catenin activity or reducing β-catenin expression to reduce disease incidence and/or increase survival. Treatment of NOD mice with quercetin, a β-catenin inhibitor, led to reduced disease incidence and a decreased inflammatory environment. Transfer of β-catenin siRNA-treated BMDC into NOD mice also reduced disease incidence. These studies reveal that β-catenin plays a role in the inflammation leading to diabetes development.vi

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The specific p38 mitogen-activated protein kinase pathway inhibitor FR167653 keeps insulitis benign in nonobese diabetic mice

Cited by 18 publications

References 32 publications

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

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