Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-18 is a cytokine with potent IFN-gamma inducing activities as well as an important mediator of Th1 polarized immune responses. In this study we demonstrated that IL-18 induces the concentration-dependent production of the proinflammatory mediators IFN-gamma, IL-6, and GM-CSF, but not the anti-inflammatory cytokine, IL-10 from peripheral blood lymphocytes in the presence of mitogen. Three neutralizing IL-18 monoclonal antibodies (MAbs) were investigated, one of which (2C10) inhibited IL-18 bioactivity with an IC50 of 0.1 nM and had a K(D) of 3.9 x 10(-11) M. A NOD/SCID mouse model engrafted with human peripheral blood lymphocytes was developed to test the in vivo efficacy of this MAb. The IFN-gamma production induced by LPS administration was inhibited approximately 90% by prior dosing of MAb 2C10. The therapeutic utility of a high-affinity IL-18 MAb may be of benefit in Th1-driven autoimmune diseases such as rheumatoid arthritis and Crohn's Disease, where elevated levels of IL-18 have been observed.
 ...
PMID:Characterization of the in vitro and in vivo activity of monoclonal antibodies to human IL-18. 1112 25

The autoimmune diabetic NOD mouse serves as a model for human type 1 diabetes. Disease development is due to islet beta cell destruction in the context of immune cell infiltration of islets and inflammatory changes throughout the pancreas. In the present study we tried to identify immune reactivity patterns in the pancreas associated with diabetes resistance in NOD-related mouse strains. The pancreata of diabetes-prone female NOD/LtJ, NOD/Bom and of genetically related but diabetes-resistant strains; NOR, NON, NON.NOD-H2g7, NOD.NON-H-2nbl were obtained at the age of 70 days for semiquantitative analysis of insulitis and of mRNA expression by reverse transcriptase PCR. In addition, the response to a single dose of cyclophosphamide for synchronizing and accelerating the progression of insulitis was determined. The progression of insulitis and immune gene expression in response to cyclophosphamide revealed characteristic differences between the six strains. NOD/LtJ and NOD/Bom mice were found significantly to upregulate pancreatic IL-12p40 and IL-18 expression after cyclophosphamide treatment, followed by an increase in IFN-gamma mRNA levels. In contrast, the two MHC-haplotype H-2nbl expressing strains either up-regulated neither IL-12/IL-18 nor IFN-gamma gene expression. The two strains sharing MHC haplotype H-2g7 expression with NOD did respond to cyclophosphamide with IL-12p40/IL-18 gene expression. However, NON.NOD-H-2g7 mice failed to progress to IFN-gamma gene expression. NOR mice progressed to IFN-gamma expression but exhibited sustained IL-4 gene expression. Only severe intra-insulitis was associated with the expression of inducible NO synthase. The comparison of diabetes-prone and diabetes-resistant strains revealed three checkpoints of immune regulation in the pancreas. The earliest checkpoint is the induction of an IL-12p40/IL-18 response in innate immune or antigen-presenting cells. The next level of control is at the induction of IFN-gamma gene expression, and a third checkpoint is the maintenance or loss of antagonistic Th2 type reactions.
 ...
PMID:Disease resistant, NOD-related strains reveal checkpoints of immunoregulation in the pancreas. 1140 10

Interleukin (IL)-1 beta and IL-18 are two cytokines associated with the immunopathogenesis of diabetes in NOD mice. Both of these cytokines are cleaved by caspase-1 to their biologically active forms. IL-1 is a proinflammatory cytokine linked to beta-cell damage, and IL-18 stimulates production of interferon (IFN)gamma in synergy with IL-12. To examine the effects produced by caspase-1 deficiency on diabetes development in NOD/Lt mice, a disrupted Casp1 gene was introduced by a speed congenic technique. Casp1(-/-) bone marrow-derived macrophages stimulated with lipopolysaccharide produced no detectable IL-18, fourfold lower IL-1 beta, and 20-30% less IL-1 alpha than macrophages from wild-type Casp1(+/+) or Casp1(+/-) controls. Unexpectedly, despite reduced IL-1 and IL-18, there was no change in the rate of diabetes or in total incidence as compared with that in wild-type NOD mice. IL-1 reportedly makes an important pathological contribution in the multidose streptozotocin model of diabetes; however, there was no difference in sensitivity to streptozotocin between NOD mice and NOD.Casp1(-/-) mice at 40 mg/kg body wt or at 25 mg/kg body wt dosage levels. These findings show that caspase-1 processing of IL-1 beta and IL-18 is not absolutely required for mediation of spontaneous or chemically induced diabetes pathogenesis in the NOD mouse.
 ...
PMID:Caspase-1 is not required for type 1 diabetes in the NOD mouse. 1469 3

IL-18 is a type 1 pro-inflammatory cytokine with structural similarities to IL-1 and in synergy with IL-12 stimulates IFN-gamma production from T lymphocytes and polarizes development and function of Th1 cells. Because IL-1, IFN-gamma, and up-regulated Th1-mediated events are involved in the pathogenesis of both human and rodent type 1 diabetes mellitus, we have evaluated the effects of a specific inhibitor of IL-18 (the IL-18bp:FcIg) on the development of accelerated forms of autoimmune diabetes in NOD mice. The data show that prolonged prophylactic treatment with IL-18bp:FcIg significantly reduced the cumulative incidence of diabetes induced in NOD mice either by adoptive transfer of diabetogenic cells or by injection with large doses of cyclophosphamide. These data provide the first in vivo evidence for the diabetogenic role of IL-18 in immuno-inflammatory diabetogenic pathways in NOD mice.
 ...
PMID:IL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosphamide-induced diabetes in NOD mouse. 1587 24

Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.
 ...
PMID:Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. 1640 88

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis. Here we describe a novel role for a caspase in dampening responses to bacterial infection. We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock. The resulting survival advantage was conferred by the ability of the caspase-12-deficient mice to clear bacterial infection more efficiently than wild-type littermates. Caspase-12 dampened the production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-18 (interferon (IFN)-gamma inducing factor) and IFN-gamma, but not tumour-necrosis factor-alpha and IL-6, in response to various bacterial components that stimulate Toll-like receptor and NOD pathways. The IFN-gamma pathway was crucial in mediating survival of septic caspase-12-deficient mice, because administration of neutralizing antibodies to IFN-gamma receptors ablated the survival advantage that otherwise occurred in these animals. Mechanistically, caspase-12 associated with caspase-1 and inhibited its activity. Notably, the protease function of caspase-12 was not necessary for this effect, as the catalytically inactive caspase-12 mutant Cys299Ala also inhibited caspase-1 and IL-1beta production to the same extent as wild-type caspase-12. In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade. In mice, caspase-12 deficiency confers resistance to sepsis and its presence exerts a dominant-negative suppressive effect on caspase-1, resulting in enhanced vulnerability to bacterial infection and septic mortality.
 ...
PMID:Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. 2725 Dec 34

Caspase-1 is activated by a variety of stimuli after the assembly of the "inflammasome," an activating platform made up of a complex of the NOD-LRR family of proteins. Caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin (IL)-1beta and IL-18, and is involved in the control of many bacterial infections. Paradoxically, however, its absence has been reported to confer resistance to oral infection by Salmonella typhimurium. We show here that absence of caspase-1 or components of the inflammasome does not result in resistance to oral infection by S. typhimurium, but rather, leads to increased susceptibility to infection.
 ...
PMID:Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. 1671 17

The NOD-like receptors have important roles in innate immunity as intracellular sensors of microbial components and cell injury. It has been proposed that these cytosolic proteins regulate the cysteine protease caspase-1 within a multiprotein complex known as the 'inflammasome'. Activation of caspase-1 leads to the cleavage and activation of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-18, as well as host-cell death. The analysis of mice that are deficient in various inflammasome components has revealed that the inflammasome is a dynamic entity that is assembled from different adaptors in a stimulus-dependent manner. Here we review recent work on the activation of the inflammasome in response to various bacterial pathogens and tissue damage.
 ...
PMID:Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. 1718 29

Francisella tularensis (F. tularensis) is a facultative intracellular pathogen that causes the systemic disease tularemia. This pathogen can replicate in the cytosol of macrophages, an ability that is linked with its virulence. We discuss recent data demonstrating that in macrophages, cytosolic Francisella induce the activation of the cysteine protease caspase-1 within a multiprotein complex called the inflammasome. NOD-like receptors (NLRs), which may have important roles in innate immunity as intracellular sensors of microbial components and cell injury, and the adaptor molecule ASC are thought to regulate caspase-1 within the inflammasome. Both ASC and caspase-1 play a critical role in host defense against Francisella infection in vivo. Activation of caspase-1 leads to the cleavage and activation of proinflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-18, as well as the induction of host cell death, which are required for innate immune defense against Francisella and other intracellular pathogens. The cytokine IFN-beta is secreted from infected cells in response to cytosolic Francisella and its signaling through the type I interferon receptor is required for activation of the inflammasome. Despite the effort of the host to induce inflammasome activation, Francisella modulates this host defense pathway, limiting its efficacy. These results highlight the role that the inflammasome plays in the tug-of-war between Francisella and the immune system.
 ...
PMID:Francisella tularensis: activation of the inflammasome. 1739 24

Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF. Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases.
 ...
PMID:NALP inflammasomes: a central role in innate immunity. 1770 4


1 2 3 4 5 6 7 8 9 10 Next >>