Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute, monophasic experimental allergic encephalomyelitis (EAE) in the Lewis rat shows pathological similarities to the human disease multiple sclerosis (MS). Rats that recover from EAE are essentially resistant to disease reinduction, unlike MS in which relapses are frequently associated with common bacterial and viral infections. As macrophage-derived interleukin (IL)-12 is a critical component of innate resistance to bacterial infection and appears to directly activate encephalitogenic T cells in vivo, the ability of this cytokine to reinduce paralysis in EAE was examined. Paralytic disease was exacerbated by intraperitoneal IL-12 administration and could be reinduced up to 1 week after recovery from the primary clinical episode. Concomitant with worsening of initial clinical signs and relapse was an increase in the ratio of macrophages to T cells in brain stem perivascular cuffs and the expression of inducible nitric oxide synthase in cells with both macrophage and microglial morphology. These findings suggest that IL-12 may contribute to macrophage-mediated disease exacerbation and relapse in patients with MS.
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PMID:Interleukin-12 induces relapse in experimental allergic encephalomyelitis in the Lewis rat. 917 84

Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.
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PMID:Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. 961 86

In these studies, we investigated whether bacterial infection of human colon epithelial cells is a sufficient stimulus to upregulate epithelial cell expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production. Human colon epithelial cells (Caco-2 and HT-29) rapidly upregulated iNOS mRNA and protein expression and NO production after infection with enteroinvasive Escherichia coli, Salmonella dublin, or Shigella flexneri but not after infection with noninvasive E. coli or an invasion-deficient mutant of S. dublin. Bacterial infection in the absence of added cytokines was as potent or more potent a stimulus of iNOS expression and NO production as stimulation of cells with combinations of cytokines known to strongly upregulate this epithelial cell response. Enteroinvasive E. coli increased epithelial NO production to a greater extent than S. dublin, although S. dublin was a stronger stimulus of epithelial cell interleukin-8 (IL-8) production. After enteroinvasive E. coli infection of polarized epithelial cell monolayers, nitrite, a stable NO end product, was released predominately into the apical compartment early after infection, whereas IL-8 was released in parallel into the basolateral compartment. These studies suggest NO and/or its redox products are an important component of the intestinal epithelial cell response to microbial infection.
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PMID:Enteroinvasive bacteria directly activate expression of iNOS and NO production in human colon epithelial cells. 972 70

Viral and bacterial infection in the central nervous system can induce nitric oxide production, which serves as a major host defense against invading microorganisms. Glucocorticoids secretion is enhanced and immune responses are diminished in stressed animals or in patients suffering depression. Using N9 microglial cells, this study tested the hypothesis that glucocorticoids and their precursors caused an impaired immune defense in animals because these compounds could inhibit microglial nitric oxide production. Results indicated that both hydrocortisone and the synthetic glucocorticoid, dexamethasone, were potent inhibitors of the microglial nitric oxide production. While glucocorticoid precursors were not as potent as hydrocortisone, the potency of these precursors increased linearly as they advanced on the biosynthesis pathway. Northern and Western blot analyses indicated that hydrocortisone and dexamethasone might interfere with the inducible nitric oxide synthase at either the transcription or at the post-translational level, depending on the concentrations used. These results suggest that glucocorticoids have the ability to block nitric oxide production by microgila, which could partially explain the impaired immune protection against infection in the central nervous system in stressed animals.
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PMID:Inhibition of microglial nitric oxide production by hydrocortisone and glucocorticoid precursors. 1095 85

This study examines the role of the signal transducer and activator of transcription 1 (STAT1) in induction of lipopolysaccharide (LPS)-stimulated gene expression both in vitro and in vivo. LPS-induced expression of an interferon (IFN)-inducible 10-kDa protein (IP-10), IFN regulatory factor-1 (IRF-1), and inducible nitric oxide synthase (iNOS) mRNAs was severely impaired in macrophages prepared from Stat1-/- mice, whereas levels of tumor necrosis factor alpha and KC (a C-X-C chemokine) mRNA in LPS-treated cell cultures were unaffected. A similar deficiency in LPS-induced gene expression was observed in livers and spleens from Stat1-/- mice. The reduced LPS-stimulated gene expression seen in Stat1-/- macrophages was not the result of reduced activation of nuclear factor kappaB. LPS stimulated the delayed activation of both IFN-stimulated response element and IFN-gamma-activated sequence binding activity in macrophages from wild-type mice. Activation of these STAT1-containing transcription factors was mediated by the intermediate induction of type I IFNs, since the LPS-induced IP-10, IRF-1, and iNOS mRNA expression was markedly reduced in macrophages from IFN-alpha/betaR-/- mice and blocked by cotreatment with antibodies against type I IFN. These results indicate that indirect activation of STAT1 by LPS-induced type I IFN participates in promoting optimal expression of LPS-inducible genes, and they suggest that STAT1 may play a critical role in innate immunity against gram-negative bacterial infection.
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PMID:Requirement for STAT1 in LPS-induced gene expression in macrophages. 1131 Aug 46

Deficient intake of zinc from the diet upregulates both uroguanylin (UG) and inducible nitric oxide synthase (iNOS) expression in rats. Because these changes influence intestinal fluid secretion and intestinal cell pathophysiology, they relate to the incidence of diarrheal disease and its reversal by zinc as well as intestinal inflammation in general. A model of moderate zinc deficiency in rats, which changes molecular indices of zinc deficiency, was used to further explore the effects of the proinflammatory cytokine interleukin (IL)-1alpha and zinc repletion on these changes. IL-1alpha has been shown to have a role in the intestinal inflammation that occurs with bacterial infection. Our results showed a permissive effect of zinc deficiency on both UG and iNOS expression. Specifically, UG expression was responsive to zinc deficiency and IL-1alpha challenge, which were additive when combined, whereas iNOS expression was upregulated by IL-1alpha only during the deficiency. Immunohistochemistry showed that the increase in UG was limited to enterocytes of the upper villus but, in contrast, the increase in iNOS was principally in cells of the lamina propria of IL-1alpha-treated rats. Cells exhibiting UG upregulation did not co-express serotonin. Repletion with zinc reversed upregulation of the iNOS gene within 1 d, whereas UG upregulation required 3-4 d to return to normal. This differential response to repletion suggests that mechanisms of UG and iNOS dysregulation are different. Dysregulation of both genes may contribute to the severity of zinc-responsive diarrheal disease and intestinal inflammatory disease.
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PMID:The permissive effect of zinc deficiency on uroguanylin and inducible nitric oxide synthase gene upregulation in rat intestine induced by interleukin 1alpha is rapidly reversed by zinc repletion. 1251 66

Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
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PMID:Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. 1256 35

Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.
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PMID:TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. 1287 39

The enzyme inducible nitric oxide synthase (iNOS) is part of the host innate defense system against bacterial infection. During chronic inflammation, like that seen with a Helicobacter pylori infection, constant nitric oxide production may lead to tissue and DNA damage, thus increasing the patient's risk for developing cancer. Several investigations on iNOS expression in H. pylori-associated gastritis have resulted in conflicting data. Therefore, we investigated the association between chronic H. pylori infection and iNOS expression in samples from stomach carcinoma patients as well as in antral biopsies from patients with H. pylori-associated gastritis. iNOS expression was analyzed by means of reverse transcriptase (RT)-PCR and quantified by competitive RT-PCR. To study in situ localization of iNOS in biopsy samples, immunohistochemistry was performed. iNOS enzyme activity was quantified using an arginine/citrulline assay. A significant increase in iNOS mRNA signal was only present in one-third of the analyzed patient biopsies with H. pylori-associated gastritis. These biopsies showed a 90% association with intestinal metaplasia and a 100% association with CagA-positive H. pylori. Intestinal metaplasia is discussed to be one step in the carcinogenesis of stomach cancer. Quantitation of iNOS transcripts and iNOS enzyme activity in non-cancerous mucosa of gastric cancer patients revealed a significant increase in iNOS transcripts and iNOS activity only in the mucosa of patients with stomach cancer of the intestinal type but not in the diffuse type. Our results support the hypothesis that CagA-positive H. pylori strains are associated with the expression and activity of iNOS, and therefore might contribute to the development of intestinal metaplasia leading to gastric cancer of the intestinal type.
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PMID:Up-regulation of inducible nitric oxide synthase in Helicobacter pylori-associated gastritis may represent an increased risk factor to develop gastric carcinoma of the intestinal type. 1476 Sep 71

In animal models of endotoxin, the excess production of NO and the reactive nitrogen species (RNS), are potent oxidant and nitrating agents, lead to lipid peroxidation, apoptosis, tissue dysfunction and injury and inactivate enzymes in many cell types. Although liver functions are well known to deteriorate following bacterial infection, the underlying specific mechanism(s) remain a matter of considerable debate. Therefore, the aim of the present study was to determine the in vivo effect of bacterial lipopolysaccharides (LPS) on Na+,K+-ATPase activity of guinea pig liver, and to investigate the possible contribution of RNS by measuring of iNOS activity and 3-nitrotyrosine (nTyr) levels. Liver Na+,K+-ATPase activity were maximally inhibited 6 h after LPS injection (p < 0.001 ). nTyr was not detectable in liver of normal control animals, but was detected markedly in LPS exposed animals. LPS treatment significantly increased iNOS activity of liver (p < 0.001). The regression analysis revealed a very close correlation between Na+,K+-ATPase activity and nTyr levels of LPS treated animals (r = -0.863, p < 0.001). Na+, K+-ATPase activity were also negatively correlated with iNOS activity (r = -0.823, p < 0.003) in inflamed tissues. Our results have strongly suggested that bacterial LPS disturbs activity of membrane Na+,K+-ATPase that may be an important component leading to the pathological consequences such as hepatocyte cell loss and dysfunction in which the production of RNS are increased as in the case of LPS challenge.
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PMID:Impaired Na+,K+-ATPase activity as a mechanism of reactive nitrogen species-induced cytotoxicity in guinea pig liver exposed to lipopolysaccharides. 1512 7


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