Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that the cytokine tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-alpha exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-alpha expression from astrocytes induced by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), and interleukin 1 beta (IL-1 beta). Astrocytes secrete TNF-alpha in response to LPS alone, and can be primed by IFN-gamma to enhance LPS-induced TNF-alpha production. IFN-gamma and IL-1 beta, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-alpha production alone, but act synergistically to stimulate astrocyte TNF-alpha expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-alpha gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-alpha mRNA and protein in response to LPS alone, yet IFN-gamma does not significantly enhance LPS-induced TNF-alpha expression, nor do they express appreciable TNF-alpha in response to the combined stimuli of IFN-gamma/IL-1 beta. In contrast, astrocytes from Lewis rats express low levels of TNF-alpha mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-gamma for subsequent TNF-alpha gene expression. Also, Lewis astrocytes produce TNF-alpha in response to IFN-gamma/IL-1 beta. The differential TNF-alpha production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-alpha expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-gamma, and IL-1 beta in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-gamma priming signals for subsequent TNF-alpha production, suggesting that differential TNF-alpha expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-alpha gene expression in response to LPS and IFN-gamma is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains. 190 Oct 78

Rejection continues to be a major cause of graft loss in small intestine transplantation (SIT). We have studied, by semiquantitative reverse transcriptase PCR (rtPCR), the intragraft expression of cytokines relevant to rejection in a rat model. Heterotopic SIT grafts were performed from Lewis x Brown Norway F1 donors into Lewis recipients. The isograft control was Lewis into Lewis. Five animals in each isograft and allograft group were sacrificed on POD 3, 5, 7, 8, 9, 10, 12, and 14. mRNA was isolated from portions of the terminal ileum and rtPCR performed to amplify message for interleukin-2 (IL-2), IL-2 receptor (IL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). Semiquantitative analysis was performed using 32P radionuclide incorporation and scintillation counting. The results were expressed as percent activity compared with beta-actin. Histologic correlation with cytokine expression was made. On POD 3 after SIT there was no evidence of rejection by histology and all cytokines studied showed no difference between the isograft and the allograft. On POD 5 the first evidence of mild rejection was seen on histology and IL-6, IFN-gamma, TNF-alpha showed a significant up regulation in the allograft that persisted through POD 14. mRNA for IL-2 was not significantly upregulated until POD 7 and persisted until POD 14. IL-2R was constitutively expressed in both isograft and allograft and was not a reliable predictor of rejection. Histologic rejection was moderately severe by POD 7 and severe between POD 8 and 14 correlating with the increasing expression of IL-6, IFN-gamma, and TNF-alpha. In summary, we have shown that increasing expression of mRNA for IL-6, IFN-gamma, and TNF-alpha not only correlated with severity of rejection but that upregulation began early when histologic evidence of rejection first occurred.
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PMID:The correlation of intragraft cytokine expression with rejection in rat small intestine transplantation. 794 Jun 88

The monoclonal antibody OX22 defines a functional split within CD4+ T cells in the rat, with OX22high cells mainly producing interleukin 2 (IL-2) and interferon gamma and responsible for delayed-type hypersensitivity responses, and OX22low cells mainly producing IL-4 and -5 and responsible for providing B cell help. There are reciprocal interactions between OX22high and OX22low cells, and it has been suggested that the OX22low subset has a role in the prevention of autoimmunity. We have used OX22 in vivo to define the role of these subsets in mercuric chloride-induced autoimmunity in the Brown Norway rat. In this model, there is polyclonal B cell activation and animals develop widespread tissue injury. Treatment of thymectomized animals with OX22 led to a profound reduction in the number of OX22high T cells in the peripheral blood. OX22-treated animals consistently developed more severe tissue injury than controls given an irrelevant antibody of the same isotype. Control animals pretreated with broad spectrum antimicrobial drugs showed milder tissue injury, but this protective effect of antimicrobials was lost in OX22-treated animals. Transfer of naive T cells to OX22-treated animals provided protection, but if T cells were depleted in vitro of OX22high cells before transfer, this effect was lost. These data provide evidence for a protective immunoregulatory role for OX22high T cells in mercuric chloride-induced autoimmunity.
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PMID:Regulatory role of OX22high T cells in mercury-induced autoimmunity in the brown Norway rat. 847 10

To assess whether Th-2 cytokines are involved in the late airway response (LR) after antigen challenge, we evaluated cytokine mRNA expression in the lungs of two strains of rats before and 8 h after saline or antigen challenge: Brown Norway (BN) rats, high IgE producers that develop LR after antigen challenge and Sprague-Dawley (SD) rats, low IgE producers that develop little LR and no increased airway responsiveness after antigen challenge. Rats were sensitized with ovalbumin (OA) and 14 days later, lungs were obtained before or after OA challenge and measurement of lung physiology for 8 h. Lung tissue was either fixed for in situ hybridization or frozen for evaluation of mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). We examined mRNA expression for interleukin-4 (IL-4), and IL-5 (Th-2 cytokines) and IL-2 and interferon gamma (IFN-gamma, Th-1 cytokines). In situ hybridization showed that cells expressing IL-4 and -5 mRNA were increased in the airways of the lungs of BN rats after OA challenge (P < 0.05) and that cells expressing mRNA for IFN-gamma and IL-2 were higher in SD than in BN rats after antigen challenge (P < 0.05). Results from PCR showed that prior to antigen challenge, BN rats expressed in their lungs mRNA for IL-4 and -5 and SD rats expressed very little mRNA for IL-5 only. After antigen challenge most BN and SD rats expressed mRNA for IL-4 and -5 but expression of mRNA for IL-2 and IFN-gamma was only found in SD rats. In conclusion, rats that develop a LR after antigen challenge preferentially increase Th-2 cytokine expression in their lungs whereas those without LRs preferentially express Th-1 cytokines. Our results support the role of Th-2 cytokines in the LR and asthma.
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PMID:Cytokine expression in the presence or absence of late airway responses after antigen challenge of sensitized rats. 881 Jun 41

Late allergic airway responses can be transferred by CD4+ T cells in the rat. To investigate the role of T-cell cytokines in these responses, we examined the expression of mRNA for Th2 (interleukin [IL]-4 and IL-5) and Th1 (IL-2 and interferon gamma [INF-gamma])-type cytokines in Brown Norway rats that were administered either antigen-primed W3/25(CD4)+ or OX8(CD8)+ T cells. Donors were actively sensitized by subcutaneous injection of ovalbumin (OVA) in the neck and T cells were obtained from the cervical lymph nodes by immunomagnetic cell sorting for administration to unsensitized rats. Control rats received bovine serum albumin (BSA)-primed CD4+ and CD8+ T cells. Two days later, recipient rats were challenged with aerosolized OVA, and bronchoalveolar lavage (BAL) was performed 8 h after challenge. BAL cells expressing mRNA for IL-2, IL-4, IL-5, and INF-gamma were analyzed using the technique of in situ hybridization. Recipients of OVA-primed CD4+ T cells had an increase in the fraction of BAL cells expressing mRNA for IL-4 and IL-5 compared with BSA-primed CD4+ or OVA-primed CD8+ cells (P < 0.001). Recipients of CD8+ T cells had an increase in INF-gamma mRNA expression after OVA challenge compared with recipients of BSA-primed-CD8+ or OVA-primed CD4+ T cells (P < 0.001). In conclusion, T-cell-dependent allergen-induced late responses are associated with the expression of mRNA for IL-4 and IL-5, indicating Th2 cell activation. Furthermore, the increased expression of INF-gamma in allergen challenge recipients of antigen-primed CD8+ T cells suggests that CD8+ T cells may be important in modulating allergic responses.
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PMID:Adoptively transferred late allergic airway responses are associated with Th2-type cytokines in the rat. 899 81

After viral bronchiolitis at an early age, Brown Norway (BN) rats develop chronic airway dysfunction consisting of inflammation, remodeling, episodic reversible obstruction, and hyperresponsiveness. We hypothesized that supplementation of interferon gamma (IFN-gamma) during viral illness would alter the inflammatory response and attenuate the postviral sequelae. Weanling rats were treated daily with aerosolized interferon gamma (IFN-gamma), from 2 d prior through 7 d after inoculation, and compared with saline-treated infected rats and with noninfected control rats. The IFN-gamma treatment had no significant effect on viral titers, growth retardation, or total bronchoalveolar leukocytes, but there was a slight decrease in lung interleukin-4 (IL-4) mRNA (p = 0.015) during the first week. Despite having minimal effects on the acute illness, the IFN-gamma had marked effects on postviral sequelae, the IFN-gamma group having less bronchiolar inflammation (p = 0.025) and fibrosis (p = 0.01), and lacking abnormalities in pulmonary resistance (p = 0.028) and dynamic compliance (p = 0.006) compared with the untreated postviral group. We conclude that IFN-gamma modulated the inflammatory response to viral illness, such that acute airway injury did not evolve into chronic airway dysfunction. If similar processes contribute to the development of human asthma, it may be possible to interrupt the progression of airway dysfunction with an early immunomodulatory intervention.
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PMID:Prevention of chronic postbronchiolitis airway sequelae with IFN-gamma treatment in rats. 1043 Jul 49

Interferon gamma is a T-helper cell (Th)-1-type cytokine that has been suggested to inhibit the development of an atopic Th2-type profile of cytokine expression. The aim of this study was to investigated the effect of exogenous rat interferon gamma on antigen-induced airway responses, and on Th1 and Th2-type cytokine messenger ribonucleic acid (mRNA) expression in the Brown Norway rat. Rats were actively sensitized to ovalbumin and 14 days later underwent an aerosolized ovalbumin challenge. Animals were intratracheally administered either interferon gamma (3,000 U) or control solvent 30 min prior to, and 2 and 4 h following, antigen challenge. Lung resistance was monitored over an 8-h time period. Using in situ hybridization and immunocytochemistry, the levels of Th1- (interleukin-12) and Th2-type (interleukin4 and -5) cytokine mRNA, and major basic protein expression in the bronchoalveolar lavage fluid of these rats 8 h after ovalbumin challenge were also determined. Administration of interferon gamma attenuated the development of the late-onset airways response in ovalbumin-sensitized antigen-challenged rats (p<0,05). The expression of interleukin-4 and -5 mRNA in the bronchoalveolar lavage fluid of interferon gamma treated rats was significantly attenuated compared to ovalbumin-challenged saline-treated controls (p<0.001). This was accompanied by a significant increase in the expression of interleukin-12 mRNA, and a reduction in eosinophil numbers. Intratracheal administration of interferon gamma modulates the allergic late-onset airways response in rats, and this is associated with a reduction in the expression of T-helper cell 2-type cytokines and an increase in interleukin-12 messenger ribonucleic acid expression within the airways. The present results support a role for interferon gamma in the pathophysiology of acute allergic airway responses, possibly by virtue of its ability to modulate T-helper cell 1- 2-type cytokine expression within the lungs.
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PMID:Interferon-gamma increases IL-12 mRNA expression and attentuates allergic late-onset airway responses in the Brown Norway rat. 1093 80

The cellular and molecular mechanisms that result in the induction of chemical respiratory sensitization are unclear, although there is evidence for the development of T helper (Th) 2 type responses and, in some cases, the production of IgE. We have compared cytokine secretion patterns stimulated by topical exposure of BALB/c strain mice or Brown Norway (BN) strain rats to the reference respiratory allergen trimellitic anhydride (TMA), or to the reference contact allergen 2,4-dinitrochlorobenzene (DNCB). Under conditions where TMA and DNCB provoke similar levels of immune activation [increases in lymph node cell (LNC) cellularity and proliferation] divergent cytokine expression patterns are elicited. TMA-activated LNC isolated from BALB/c mice or BN rats elaborated high levels of the Th2-type cytokines interleukin (IL)-10 and IL-13, but relatively little of the Th1-type cytokines IL-12 or interferon gamma. For LNC derived from both species there was a requirement for restimulation in vitro with the mitogen concanavalin A for IL-4 production. Generally, DNCB-stimulated LNC displayed the converse type 1 cytokine phenotype. The cytokine secretion profiles of LNC isolated from BN rats were considerably more variable than those observed for LNC from BALB/c mice. Statistically significant differences (P<0.01) between DNCB- and TMA-activated LNC were recorded for all cytokines in BALB/c strain mice. For the BN rat, differences reached statistical significance (P<0.01) only for the expression of IL-4 and IL-13. These data demonstrate that the intrinsic ability of DNCB and TMA to promote preferential Th1- and Th2-type responses, respectively, is species-independent and provide further evidence that chemical respiratory allergens are associated with polarized Th2-type responses. For the prospective assessment of chemical respiratory allergens as a function of induced cytokine secretion profiles, however, these data suggest that the use of the BALB/c strain mouse will provide the more robust method.
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PMID:Cytokine fingerprinting of chemical allergens: species comparisons and statistical analyses. 1241 3

Nitric oxide (NO), an important cell signaling molecule, is considered a marker of inflammatory response and is elevated in asthmatics. This study investigated the effects of montelukast (a leukotriene receptor antagonist) on iNOS expression and activity in a Brown Norway (BN) rat allergic inflammation model and in L2 lung epithelial cells. Allergic inflammation was induced by ovalbumin (OVA) injection in BN rats followed by treatment with either montelukast or dexamethasone (DX). Allergen inhalation was performed, and post-allergen Penh was measured 5 min after the challenge. Cysteinyl leukotriene levels were measured in bronchoalveolar lavage (BAL) fluid and lung iNOS expression and activity determined. These parameters were also measured in cytokine stimulated L2 lung epithelial cells. iNOS expression was significantly higher in OVA challenged rats compared to the naive, DX, and montelukast treated groups, as confirmed by immunohistochemistry and Western blot analysis. However, no significant differences in NOS activity were found. Cysteinyl leukotriene measured in BAL was significantly higher in all OVA challenged rats compared to naive controls. Incubation of L2 cells with a mixture of interferon gamma (IFNgamma), lipopolysaccharide (LPS), and tumor necrosis factor (TNFalpha) resulted in high levels of nitrite formation resulting from iNOS induction. Treatment of cytokine stimulated cells with DX or montelukast significantly decreased iNOS expression and activity. No detectable cysteinyl leukotrienes were found in the supernatant fluid of L2 cells. This study confirms the ability of montelukast to modulate iNOS function and raises the possibility that changes in iNOS expression and activity may occur via pathways independent of cysteinyl leukotrienes.
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PMID:A leukotriene receptor antagonist modulates iNOS in the lung and in a leukotriene-free cell model. 1455 27

Early nutritional events have the potential to affect health outcomes in later life including the development of allergy. Food allergy is usually the first manifestation of allergy. Breast-feeding has been associated with a protective effect against the development of allergy, but the evidence is contradictory and the mechanisms involved are not clear. We hypothesize that milk cytokines, such as transforming growth factor beta (TGF-beta), play a role in regulating immune responses to dietary antigens. Using a rat pup model of gastrostomy feeding, the immune response profile, at weaning and post-weaning, of allergy-prone Brown Norway rats fed formula supplementation with TGF-beta was assessed. We show that feeding formula to allergy-prone rat pups results in increased total IgE immunoglobulin, beta-lactoglobulin (BLG) IgG1 antibody, and mucosal mast cell activation, as measured by serum rat mast cell protease II (RMCPII) levels in the gut. Supplementation of formula with physiological levels of TGF-beta down-regulated the BLG IgG1 response as well as total IgE and mucosal mast cell activation. Supplementation of formula also resulted in an increase in Th1 cytokines, interleukin (IL)-18, IL-12p40, IL-12p35, and interferon gamma (IFN-gamma) and an increase in IL-10. In conclusion, TGF-beta supplementation of formula moved the immune response profile of allergy prone (Th2 type) rat pups toward a Th1 profile in the suckling period. Importantly, this immune profile persisted after weaning when TGF-beta was no longer present in the diet.
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PMID:Effects of transforming growth factor-beta and formula feeding on systemic immune responses to dietary beta-lactoglobulin in allergy-prone rats. 1662 76


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