Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha as well as T cell derived IL-2 and interferon (IFN)-gamma. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-gamma production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-gamma inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor beta (TGF-beta) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.
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PMID:Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. 971 47

The mechanisms whereby trypanotolerant N'Dama cattle control infection with Trypanosoma congolense are unknown. Previous studies have suggested that the monocytes of N'Dama cattle are more highly activated during infection than those of trypanosusceptible Boran cattle. However, we have recently reported that the monocytes of Boran cattle have a reduced capacity to secrete nitric oxide during trypanosome infection. We therefore evaluated the production of nitric oxide by monocytes of trypanotolerant N'Dama cattle infected with T. congolense in response to interferon-gamma, bacterial lipopolysaccharide or trypanosome antigens. Interferon-gamma-induced nitric oxide production was decreased between days 25 and 76 of infection, while lipopolysaccharide-induced secretion of nitric oxide was increased at days 13 and again at day 76 post-infection. Trypanosome antigens did not elicit nitric oxide production. Analysis of interleukin-10 mRNA transcription in peripheral blood leucocytes revealed an increase at time points that coincided with decreased interferon-gamma-induced nitric oxide synthesis. In contrast, interferon-gamma mRNA expression was not changed during infection while tumour necrosis factor-alpha was slightly reduced at day 32 post-infection. Recombinant interleukin-10 suppressed interferon-gamma-induced nitric oxide and tumour necrosis factor-alpha secretion, but not lipopolysaccharide-induced nitric oxide secretion in cultures of peripheral blood mononuclear cells and monocytes of uninfected cattle. These results suggest that the nitric oxide response of monocytes to IFN-gamma but not lipopolysaccharide, is suppressed during infection. The kinetics of the upregulation of interleukin-10 and its biological activity indicate a possible association with the depression of nitric oxide production and control of tumour necrosis factor-alpha.
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PMID:Trypanosoma congolense infection of trypanotolerant N'Dama (Bos taurus) cattle is associated with decreased secretion of nitric oxide by interferon-gamma-activated monocytes and increased transcription of interleukin-10. 976 9

Neospora caninum is a coccidian parasite of veterinary importance by causing abortion or stillbirth in cattle among other problems in diverse animal species. We assessed an experimental murine model for its suitability to study the immune response to N. caninum infection. Thus, wild-type (wt) C57BL/6 mice and B-cell (and consequently antibody)-deficient microMT mice were infected with N. caninum tachyzoites and sacrificed at days 10, 24 and 29-44 post infection (dpi). Various organs were collected for parasitological and pathological analysis, spleen and serum for immunological investigations. Splenocytes were in vitro-stimulated with N. caninum (NC)- and T. gondii-antigens for assessing T cell proliferation and cytokine production. While wt mice were resistant to disease, microMT mice died starting from 29 dpi onwards. Histological examination of brain tissue from microMT mice exhibited a high infection intensity with multifocal necrotic cerebral lesions, which were absent in the brains of wt mice. NC antigen-stimulated spleen cells of both wt and microMT mice infected with N. caninum showed a marked proliferative depression at 10 dpi. At 24 dpi, this immunosuppression was still maintained in microMT mice whereas it was restored in wt mice. Stimulated splenocytes of infected microMT mice secreted significantly less IFN-gamma and less IL-10 than corresponding wt splenocytes. For IL-10, this difference increased with time. The susceptibility of microMT mice appeared associated to B-cell deficiency, allowing the persistent spread of the parasite causing immunosuppression and finally resulting in a lethal outcome of infection.
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PMID:Susceptibility of B-cell deficient C57BL/6 (microMT) mice to Neospora caninum infection. 1032 Jun 20

A number of studies documented that the heavy metals are not only toxic for the organisms but they may modulate immune responses. The immunomodulatory activity was proved in several in vivo and in vitro model systems. In the current study, immunomodulatory activities of lead and cadmium are presented. The viability of both lymphocytes and macrophages was affected by heavy metals in a dose- and time-dependent manner. In the case of lead, the depression of N-oxide production closely correlated with increased blast transformation of spleen cells induced by concanavalin A (ConA). On the contrary, cadmium suppressed the production of N-oxides but stimulated significantly the proliferation of spleen cells. The production of cytokines by lymphocytes and macrophages was dependent on the in vitro model used. Generally, the treatment of macrophages with lead results in disregulation of the production of proinflammatory cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin 1alpha (IL-1alpha) and interleukin 6 (IL-6)] and preferential production of Th1 type of cytokines (IFN-gamma and IL-2). Cadmium seemed to trigger the Th2 cytokine regulatory pathway [interleukin 4 (IL-4), interleukin 10 (IL-10)]. The results suggest the metal-induced changes in immunoregulatory mechanism of host with potentially severe clinical consequences.
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PMID:The immunomodulatory effect(s) of lead and cadmium on the cells of immune system in vitro. 1069 59

Recent experimental studies have found gender differences in the immune response after hemorrhagic shock with an enhanced immune function and lower mortality after subsequent sepsis in females than in males. Interleukin-10 (IL-10) has been shown to play a potential role in the treatment of early proinflammatory state after hemorrhagic shock. Although studies showed beneficial effects of the treatment with IL-10, it remains unclear whether the effects are gender related. To study this, male and female CBA/J mice were subjected to hemorrhage (35+/-5 mmHg for 90 min and fluid resuscitation) or sham operation. At resuscitation, each received either recombinant murine IL-10 (rmIL-10) or placebo i.p. At 48 h after resuscitation, peritoneal macrophages (pMphi) and splenocytes were harvested. IL-1beta and IL-12 release by pMphi and splenocyte proliferation and splenocyte IL-2 and interferon (IFN)-gamma release capacity were assessed. Interleukin-10 plasma levels were not increased after rmIL-10 treatment. The results indicate that rmIL-10 treatment restores depressed immune response (splenocyte proliferation, IFN-gamma, IL-1beta in males after hemorrhagic shock. In contrast, the immune responses after shock in females were not influenced by rmIL-10, with the exception of depressed splenocyte proliferation. In addition, sham-operated male mice treated with rmIL-10 showed immune depression compared with the placebo group. Thus, administration of rmIL-10 during resuscitation after hemorrhage produces salutary effects on the depressed immune responses in males but did not further enhance the immune functions in females under those conditions.
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PMID:Gender-related therapy: early IL-10 administration after hemorrhage restores immune function in males but not in females. 1102 56

The role of CD4(+) vs CD8(+) T cells in contact hypersensitivity (CHS) remains controversial. In this study, we used gene knockout (KO) mice deficient in CD4(+) or CD8(+) T cells to directly address this issue. Mice lacking either CD4(+) or CD8(+) T cells demonstrated depressed CHS responses to dinitrofluorobenzene and oxazolone compared with wild-type C57BL/6 mice. The depression of CHS was more significant in CD8 KO mice than in CD4 KO mice. Furthermore, in vivo depletion of either CD8(+) T cells from CD4 KO mice or CD4(+) T cells from CD8 KO mice virtually abolished CHS responses. Lymph node cells (LNCs) from hapten-sensitized CD4 and CD8 KO mice showed a decreased capacity for transferring CHS. In vitro depletion of either CD4(+) T cells from CD8 KO LNCs or CD8(+) T cells from CD4 KO LNCs resulted in a complete loss of CHS transfer. LNCs from CD4 and CD8 KO mice produced significant amounts of IFN-gamma, indicating that both CD4(+) and CD8(+) T cells are able to secrete IFN-gamma. LNCs from CD8, but not CD4, KO mice were able to produce IL-4 and IL-10, suggesting that IL-4 and IL-10 are mainly derived from CD4(+) T cells. Intracellular cytokine staining of LNCs confirmed that IFN-gamma-positive cells consisted of CD4(+) (Th1) and CD8(+) (type 1 cytotoxic T) T cells, whereas IL-10-positive cells were exclusively CD4(+) (Th2) T cells. Collectively, these results suggest that both CD4(+) Th1 and CD8(+) type 1 cytotoxic T cells are crucial effector cells in CHS responses to dinitrofluorobenzene and oxazolone in C57BL/6 mice.
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PMID:CD4+ Th1 and CD8+ type 1 cytotoxic T cells both play a crucial role in the full development of contact hypersensitivity. 1112 Jul 99

It has been established that thyrotropin-releasing hormone (TRH) affects several aspects of immunoreactivity, e.g. production of pro-inflammatory cytokines, and enhances therapeutic efficiency of classic tricyclic antidepressants. On the other hand, it has been suggested that pro-inflammatory cytokines play a role in the etiology of depression, whereas the therapeutic efficacy of antidepressants is related to their negative immunoregulatory effect. In order to verify the hypothesis that the TRH-induced increase in the therapeutic efficiency of classic tricyclic antidepressants results from synergistic inhibitory effects of those two agents on the secretion of pro-inflammatory cytokines, we studied the effect of imipramine appliedjointly with TRH on the production of IFN-gamma and IL-10 by human whole blood cells stimulated in vitro by mitogens. A significant decrease in the production of IFN-gamma and IL-10 cytokines, by 36% and 34%, respectively, was observed in cells stimulated with mitogens and co-incubated with imipramine and TRH (either given at a dose of 10(-5) M). Under the same conditions, TRH alone did not change the production of those cytokines. Furthermore, imipramine alone decreased, not statistically significantly, though, the production of IFN-gamma. Hence our data only partly support the above-mentioned hypothesis, since TRH and imipramine applied jointly suppress the production of both the pro-inflammatory IFN-gamma and the anti-inflammatory IL-10 cytokines.
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PMID:Suppressive effect of TRH and imipramine on human interferon-gamma and interleukin-10 production in vitro. 1133 44

Tumor development and aging can each alter immune competence. The present study aimed to determine the impact of Lewis lung carcinoma (LLC) presence on immune parameters of middle-aged (averaging 6.5 months) versus aged (averaging 21.3 months) mice. An age-associated decline in the CD4+ cell frequency was seen in freshly isolated spleen and lymph node cells, as well as in cultures stimulated with immobilized anti-CD3. This decline was not further exacerbated by tumor presence. What was prominently inhibited by tumor was the capacity of either splenic or lymph node CD4+ cells to become stimulated to express IFN-gamma. Spleen and lymph node cultures from aged tumor-bearing mice had the lowest frequency of CD4+IFN-gamma+ cells and the least amount of secreted IFN-gamma. CD8+ cells were not affected by aging, but tumor presence reduced the induction of CD8+IFN-gamma+ cells in lymph node cultures. We previously showed that LLC growth stimulates myelopoiesis, as seen by splenomegaly and the mobilization of immune inhibitory CD34+ progenitor cells. Tumor presence in middle-aged mice reduced spleen cell blastogenesis, which was mediated by CD34+ cells. Aged mice had reduced blastogenesis, and this was further reduced by presence of tumor. However, neither the age-associated immune dysfunction nor the tumor-induced immune suppression in aged mice was due to CD34+ progenitor cells. These studies show how tumor presence can further compromise the immune dysfunction that accompanies aging. In addition, they show that aging impacts on the mechanisms by which tumors inhibit T-cell capabilities, with myelopoiesis-associated CD34+ cells mediating the immune depression of middle-aged tumor-bearers and an independent mechanism being responsible for the immune depression in aged tumor-bearing mice.
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PMID:Impact of aging on immune modulation by tumor. 1157 May 85

Human visceral leishmaniasis (VL) results in a severe and potentially fatal systemic disease, accompanied by cellular immune depression. The production of IL-10 correlates with ongoing disease and it has been suggested that the cellular immune depression that accompanies active disease may be due to a predominance of IL-10 production rather than a lack of IFN-gamma production, which is essential for optimal macrophage activation and parasite elimination. To examine the role of IL-10 in resistance during L. donovani infection (a causative agent of VL), the course of infection was examined in mice lacking the gene for IL-10. BALB/c IL-10-/-, as well as C57BL/6 IL-10-/- mice, were highly resistant to L. donovani infection, as evidenced by liver parasite burdens which were tenfold lower than those in control mice after 14 days of infection. Enhanced resistance was accompanied by increased production of IFN-gamma and nitric oxide in BALB/c IL-10-/- mice. Susceptibility to infection in BALB/c IL-10-/- mice was enhanced following in vivo treatment with a neutralizing antibody to IFN-gamma or IL-12. Together these studies demonstrate for the first time that IL-10 is a critical component of the immune response that inhibits resistance to L. donovani.
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PMID:IL-10 mediates susceptibility to Leishmania donovani infection. 1159 59

The object of the study was to determine whether male and female sex steroids produce divergent effects on Th1 and Th2 cytokine release following trauma-haemorrhage. Recent studies indicate that androgens are responsible for the depressed splenocyte Th1 cytokine release in males following trauma-haemorrhage. In contrast, female mice maintain their Th1 cytokine release capacity following trauma-haemorrhage. Nonetheless, the effect of male and female sex steroids on Th1 and Th2 cytokine release following trauma-haemorrhage remains unknown. Male C3H/HeN mice were castrated and treated with pellets containing either vehicle, 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (estradiol), or a combination of both steroid hormones, for 14 days prior to soft-tissue trauma (i.e. laparotomy) and haemorrhagic shock (35+/-5 mmHg for 90 min followed by adequate fluid resuscitation) or sham operation. Untreated male and female mice, as well as DHT treated female mice, served as control groups. Twenty-four hours later the animals were sacrificed, plasma obtained and splenocytes harvested. Plasma DHT and estradiol levels in treated animals were comparable with intact male and female mice, respectively. A significant depression of splenocyte Th1 cytokines, i.e. IL-2, IFN-gamma, was observed in DHT treated castrated animals, DHT treated females, and untreated males following trauma-haemorrhage, as opposed to maintained Th1 cytokine release in estradiol treated and estradiol/DHT treated castrated animals and females. The release of the anti-inflammatory cytokine IL-10 was markedly increased in DHT treated mice and males subjected to trauma-haemorrhage compared to shams, but decreased in estrogen treated mice and females under such conditions. These results suggest that male and female sex steroids differentially affect the release of Th1 and Th2 cytokines following trauma-haemorrhage and should be further studied for their potential to modulate splenocyte function in trauma victims.
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PMID:Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-haemorrhage. 1166 83


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