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)

After parainfluenza type 1 (Sendai) virus infection as weanlings, Brown Norway (BN), unlike Fischer 344 (F344), rats develop an asthma-like phenotype. Reduced postinfection interferon (IFN)-gamma levels in bronchoalveolar lavage fluid from BN weanlings and the prevention of chronic airway sequelae in BN rats by IFN-gamma treatment led to the hypothesis that cells from BN weanlings have a reduced ability to secrete IFN-gamma. After stimulation with Sendai virus or interleukin (IL)-12, splenocytes from uninfected BN weanlings secreted significantly less IFN-gamma than did splenocytes from F344 weanlings (P < 0.005), as determined by enzyme-linked immunosorbent assay. Because levels of potential IFN-gamma-secreting cells in the spleen differed between the strains, natural killer (NK) cells, an important IFN-gamma source during early antiviral responses, were purified from spleens of uninfected weanlings. When stimulated with IL-12, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.001). Incubation of NK cells from either strain with IL-12 and IL-18 resulted in synergistic increases in IFN-gamma production, but BN cells still secreted significantly less IFN-gamma than did F344 cells (P < 0.05). Similarly, after incubation with either IFN-alpha or IFN-alpha plus IL-18, BN NK cells secreted significantly less IFN-gamma than did F344 NK cells (P < 0.05). Therefore, reduced IFN-gamma secretion by NK cells in BN weanlings may play a role in the development of postviral chronic airway dysfunction.
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PMID:Reduced interferon-gamma secretion by natural killer cells from rats susceptible to postviral chronic airway dysfunction. 1115 53

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.
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PMID:Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787. 1196 Oct 80

Abstract: Nitric oxide (NO) inhibits T cell proliferation. We demonstrate that the action of NO on T cell proliferation is different for Lewis and Brown Norway (BN) rats. Splenocytes from Lewis rats consistently showed higher proliferation against concanavalin A than splenocytes from BN rats did. In contrast, NO production was higher in BN rats than in Lewis rats. A depletion of adherent cells increased proliferation in BN rats to a level similar to that in Lewis rats. Thus NO produced by adherent splenocytes could be considered to inhibit proliferation. The addition of NG-monomethyl-L-arginine, a potent inhibitor of NO production, increased proliferation in Lewis rats, but much less so in BN rats. Similar results were obtained by the addition of anti-interferon (IFN)-gamma. It is surprising that, low doses of sodium nitroprusside, an NO donor, increased proliferation in BN rats but not in Lewis rats. To investigate the mechanism of differential NO production between the two strains, splenocytes were stimulated with IFN-gamma. The early signaling event evaluated by the phosphorylation of Stat-1 was similar in both strains, whereas inducible NO synthase (iNOS) mRNA expression seemed more sustained in BN rats. Thus the differential production of NO might be related to the differential transcriptional regulation of iNOS. Altogether, genetic background might be involved in sensitivity to the inhibitory function of NO for T cell proliferation and NO production.
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PMID:Genetic background determines sensitivity to the inhibitory function of NO on T cell proliferation and the amounts of NO production mediated through IFN-gamma. 1236 19

Previously, we showed that diesel exhaust particles (DEPs) suppressed pulmonary clearance of Listeria monocytogenes (Listeria) and inhibited the phagocytosis of alveolar macrophages and their response to Listeria in the secretion of interleukin (IL)-1 beta, tumor necrosis factor alpha, and IL-12. In this report we examined the effects of DEPs and/or Listeria on T-cell development and secretion of IL-2, IL-6, and interferon (IFN)-gamma. We exposed Brown Norway rats to clean air or DEPs at 50 or 100 mg/m3 for 4 hr by nose-only inhalation and inoculated with 100,000 Listeria. Lymphocytes in the lung-draining lymph nodes were isolated at 3 and 7 days postexposure, analyzed for CD4+ and CD8+ cells, and measured for cytokine production in response to concanavalin A or heat-killed L. monocytogenes. Listeria infection induced lymphocyte production of IL-6. At 7 days postinfection, lymphocytes from Listeria-infected rats showed significant increases in CD4+ and CD8+ cell counts and the CD8+/CD4+ ratio and exhibited increased production of IFN-gamma and IL-2 receptor expression compared with the noninfected control. These results suggest an immune response that involves the action of IL-6 on T-cell activation, yielding Listeria-specific CD8+ cells. DEP exposure alone enhanced lymphocyte production of both IL-2 and IL-6 but inhibited lymphocyte secretion of IFN-gamma. In rats exposed to 100 mg/m3 DEPs and Listeria, a 10-fold increase occurred in pulmonary bacterial count at 3 days postinfection when compared with the Listeria-only exposure group. The isolated lymphocytes showed a significant increase in the CD4+ and CD8+ cell counts and the CD8+/CD4+ ratio and exhibited increased IL-2 responsiveness and increased capacity in the secretion of IL-2, IL-6, and IFN-gamma. This T-cell immune response was sufficient to allow the Brown Norway rats to clear the bacteria at 7 days postinfection and overcome the down-regulation of the innate immunity by the acute DEP exposure.
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PMID:Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust particles (DEPs). II. Effects of DEPs on T-cell-mediated immune responses in rats. 1267 10

Genetic background determines the histological features of experimental immune-mediated blepharoconjunctivitis (EC) in rats, which is a model for human allergic conjunctivitis (AC). A great number of lymphocytes predominate in EC of Lewis rats, while less lymphocytes and more eosinophils are present in that of Brown Norway (BN) rats. Although this difference could be attributed to their systemic Th1/Th2 dominancy, it remains unclear whether some regulatory mechanisms may exist in the inflammatory site in the conjunctiva. Here, we aim to investigate this hypothesis by comparing the expression levels of inflammatory mediators in the conjunctiva between the two strains. EC was induced in Lewis and BN rats by transfer of ovalbumin (OVA)-specific CD4(+) T-cell lines followed by eye drops of OVA as antigen challenge, and then was clinically and histologically evaluated. Reverse-transcription (RT)-PCR was performed to compare the expressions of cytokines and cytokine receptors (Rs) in conjunctivas of both strains of rats either with or without EC. To confirm the biological significance of interferon (IFN)-gamma R expression, phosphorylation of signal transducers and activators of transcription (STAT)-1 was examined in the conjunctivas, followed by subconjunctival injection of IFN-gamma. BN T cells contained interleukin (IL)-4 and IFN-gamma, while Lewis T cells expressed no IL-4. Transfer of those cells induced more severe EC in Lewis rats. RTPCR using naive conjunctivas detected more IL-4, IFN-gamma, and IFN-gamma R beta-chain RNA expression in BN rats. After the EC induction, BN rats expressed significantly higher amounts of IFN-gamma R beta-chain, and upregulation of interferon regulatory factor (IRF)-1 was observed. Phosphorylation of STAT-1 was more remarkable in BN rats. The findings demonstrate differential expression of IFN-gamma R and signaling through IFN-gamma in the conjunctiva between the two strains. This may be due to differences in histopathological character between the two strains.
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PMID:Differential expression and signaling of IFN-gamma in the conjunctiva between Lewis and Brown Norway rats. 1460 45

Diesel exhaust particles (DEP) have been shown to alter pulmonary immune responses to bacterial infection. Exposure of rats to 100 mg/m(3) DEP for 4 h was found to aggravate Listeria monocytogenes(Listeria) infection at 3 days postinfection, but the bacteria were largely cleared at 7 days postinfection due to the development of a strong T cell-mediated immunity. In the present study, we examined the effects of repeated DEP exposure at lower doses on pulmonary responses to bacterial infection. Brown Norway rats were exposed to DEP by inhalation at 20.62 +/- 1.31 mg/m 3 for 4 h/day for 5 days, followed by intratracheal inoculation with 100,000 Listeria at 2 h after the last DEP exposure. DEP-exposed rats showed a significant increase in lung bacterial load at both 3 and 7 days postinfection. The repeated DEP exposure was shown to suppress both the innate, orchestrated by alveolar macrophages (AM), and T cell-mediated responses to Listeria. DEP inhibited AM production of interleukin- (IL-) 1beta, tumor necrosis factor- (TNF-) alpha, and IL-12 but enhanced Listeria-induced AM production of IL-10, which has been shown to prolong the survival of intracellular pathogens such as Listeria. DEP exposure also suppressed the development of bacteria-specific lymphocytes from lung-draining lymph nodes, as indicated by the decreased numbers of T lymphocytes and their CD4(+) and CD8(+) subsets. Furthermore, the DEP exposure markedly inhibited the Listeria-induced lymphocyte secretion of IL-2 at day 7, IL-10 at days 3 and 7, and interferon- (IFN-) gamma at days 3 to 10 postinfection when compared to air-exposed controls. These results show a sustained pattern of downregulation of T cell-mediated immune responses by repeated low-dose DEP exposure, which is different from the results of a single high-dose exposure where the acute effect of DEP aggravated bacteria infection but triggered a strong T cell-mediated immunity.
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PMID:Suppression of cell-mediated immune responses to listeria infection by repeated exposure to diesel exhaust particles in brown Norway rats. 1465 13

Conjunctival papillary formation and corneal damage, which are seen in severe types of allergic conjunctival diseases, are mediated by eosinophils. Eosinophils themselves are not able to recognize a specific antigen (Ag) and thus, Ag-specific T cells are thought to be important for eosinophilic infiltration into the conjunctiva. Cytokines, which are produced by Ag-specific T cells followed by Ag recognition, are considered to be involved in eosinophilic infiltration. Therefore, we investigated the involvement of cytokines, which are produced by immunocompetent cells and conjunctival cells, in the infiltration of inflammatory cells into the conjunctiva, using an animal model for allergic conjunctival diseases (experimental immune-mediated blepharoconjunctivitis, EC). The peak of expression of Th 2 cytokines such as interleukin (IL)-4 in the rat conjunctiva was 6 and 12 hours after Ag challenge. In contrast, expression of Th1 cytokines such as interferon (IFN)-gamma persisted up to 48 hours after Ag challenge. The kinetic change of IL-4 was concordant with eosinophilic infiltration into the conjunctiva and that of IFN-gamma was in accord with infiltration of macrophages. To investigate the roles of these cytokines, we induced conjunctivitis in cytokine knockout mice. The infiltration of inflammatory cells was attenuated in IL-4 knockout mice, whereas it was augmented in IFN-gamma knockout mice. To further elucidate the roles of these cytokines, we induced and analyzed EC in Brown Norway rats. Eosinophilic infiltration was increased in EC induced by the transfer of T cells, which were stimulated by IL-4. In addition, systemic treatment with IFN-gamma inhibited eosinophilic infiltration in EC induced by active immunization, but did not affect infiltration of inflammatory cells in EC induced by passive immunization. These results demonstrate that IL-4 and IFN-gamma are involved in the infiltration of eosinophils and macrophages, respectively. In addition, IFN-gamma exerts its suppressive effects on the development of EC only during the induction phase of EC. Further detailed studies investigating the roles of cytokines in the conjunctiva will elucidate the developing mechanism of allergic conjunctival diseases. These studies will provide important clues for a therapeutic approach in targeting cytokines.
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PMID:[Roles of cytokines in the development of severe allergic conjunctival diseases: analyses using animal models]. 1558 53

Studies have shown that exposure to diesel exhaust particles (DEP) suppresses pulmonary host defense against bacterial infection. The present study was carried out to characterize whether DEP exposure exerts a sustained effect in which inhaled DEP increase the susceptibility of the lung to bacterial infection occurring at a later time. Brown Norway rats were exposed to filtered air or DEP by inhalation at a dose of 21.2 +/- 2.3 mg/m3, 4 h/day for 5 days, and intratracheally instilled with saline or 100,000 Listeria monocytogenes (Listeria) 7 days after the final DEP exposure. Bacterial growth and cellular responses to DEP and Listeria exposures were examined at 3 and 7 days post-infection. The results showed that inhaled DEP prolonged the growth of bacteria, administered 7 days post DEP exposure, in the lung as compared to the air-exposed controls. Pulmonary responses to Listeria infection were characterized by increased production of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-12, and IL-10 by alveolar macrophages (AM) and increased presence of T lymphocytes and their CD4+ and CD8+ subsets in lung draining lymph nodes that secreted elevated levels of IL-2, IL-6, IL-10, and interferon (IFN)-gamma. Diesel exhaust particles were found to inhibit Listeria-induced production of IL-1beta and TNF-alpha, which are responsible for the innate immunity, and IL-12, which initiates the development of T helper (Th)1 responses, but enhance Listeria-induced AM production of IL-10, which prolongs Listeria survival in these phagocytes. The dual action of DEP on AM production of IL-12 and IL-10 correlated with an inhibition of the development of bacteria-specific T lymphocytes by DEP. Cytokine production by lymphocytes from DEP- and Listeria-exposed rats showed a marked decrease in the production of IL-2, IL-10, and IFN-gamma compared to Listeria infection alone, suggesting either that DEP inhibit the production of cytokines by lymphocytes or that these lymphocytes contained T-cell subsets that are different from those of Listeria infection alone and less effective in mediating Th1 immune responses. This study demonstrates that inhaled DEP, after a 7-day resting period, increase the susceptibility of the lung to bacterial infection occurring at a later time by inhibiting macrophage immune function and suppressing the development of T-cell-mediated immune responses. The results support the epidemiological observations that exposure to DEP may be responsible for the pulmonary health effects on humans.
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PMID:Sustained effect of inhaled diesel exhaust particles on T-lymphocyte-mediated immune responses against Listeria monocytogenes. 1610 54

Toxoplasmosis is a ubiquitous parasitic infection causing a wide spectrum of diseases. It is usually asymptomatic but can lead to severe ocular and neurological disorders. Among the small-animal models available to study factors that determine susceptibility to toxoplasmosis, the rat appears to be rather similar to humans, particularly in terms of resistance to acute infection. Here, we demonstrate that the Lewis (LEW) rat strain displays an unexpected refractoriness to Toxoplasma infection. Complete resistance was assessed by both negative anti-Toxoplasma serology and lack of detection of the parasite during the course of infection. In this model, sex, age, major histocompatibility complex, and inoculum size had no effect on resistance. Interestingly, progeny from F(1) hybrid crosses between Fischer (F344) or Brown Norway susceptible rats and LEW resistant rats were also fully resistant, showing a dominant effect of the gene or set of genes. Furthermore, resistance of the LEW rat was shown to be dependent on hematopoietic cells and partially abrogated by neutralization of endogenous gamma interferon. To our knowledge, this is the first observation of a rodent strain that is refractory to Toxoplasma infection. This model is therefore an attractive and powerful tool to dissect host genetic factors involved in susceptibility to toxoplasmosis.
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PMID:Innate refractoriness of the Lewis rat to toxoplasmosis is a dominant trait that is intrinsic to bone marrow-derived cells. 1617 79

The aim of this study was to test whether donor and recipient gender influence the development of obliterative airway disease in an established rat model of human bronchiolitis obliterans. Rat tracheas were transplanted from male and female Brown-Norway donors into male and female Lewis recipients. Grafts were harvested at days 7, 14 and 21 for morphometric studies and molecular analysis by real-time PCR. At each time point, both epithelial injury and the extent of luminal occlusion of the tracheal allografts were similar between the groups. Furthermore, intragraft mRNA expression for transforming growth factor (TGF)-beta1, interleukin (IL)-2 and interferon (INF)-gamma did not differ between the groups. Our data suggest that gender has no impact on the development of obliterative airway disease in this transplant model.
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PMID:No gender difference in development of obliterative airway disease in rat tracheal allografts. 1685 78


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