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

Interleukin (IL)-4 has been implicated in the pathogenesis of leishmaniasis in a murine model. Experiments were done to examine the effect of IL-4 on cytokine activation of macrophages. Interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and IL-3 activate macrophages to inhibit replication of leishmaniae. IL-4 abrogated in a dose- and time-dependent manner the induction of antileishmanial activity by these cytokines. The depression of oxidative burst capacity is one mechanism by which IL-4 inhibits macrophage activation. IL-4 diminished in a dose- and time-dependent manner the TNF alpha enhancement of oxidative capacity. Pretreatment with IL-4 for 48, 24, or 0 h, respectively, inhibited the generation of superoxide induced by TNF alpha by 90%, 60%, and 40%. Furthermore, IL-4 abrogated the enhancement of oxidative capacity by IFN-gamma, GM-CSF, and IL-3. These data suggest that IL-4 is a potent deactivator of macrophage antimicrobial functions and may contribute to the pathogenesis of visceral leishmaniasis.
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PMID:Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity. 130 48

Natural Killer cell Stimulatory Factor (NKSF) or interleukin-12 (IL-12) is a heterodimeric cytokine of 70 kDa formed by a heavy chain of 40 kDa (p40) and a light chain of 35 kDa (p35). Although it was originally identified and purified from the supernatant of Epstein-Barr virus-transformed B cell lines, it has been shown that among peripheral blood cells NKSF/IL-12 is predominantly produced by monocytes, with lower production by B cells and other accessory cells. The most powerful inducers of NKSF/IL-12 production are bacteria, bacterial products and parasites. In addition to the biologically active p70 heterodimer, the cells producing NKSF/IL-12 also secrete a large excess of monomeric p40, a molecule with no demonstrable biological activity. NKSF/IL-12 is active on T lymphocytes and NK cells on which it induces production of lymphokines, enhancement of cytotoxic activity and mitogenic effects. NKSF/IL-12 induces T and NK cells to produce IFN-gamma and synergizes with other IFN-gamma inducers in this effect. In vitro, and probably in vivo, NKSF/IL-12 is required for optimal IFN-gamma production. When human lymphocytes are stimulated with antigens in vitro, addition of exogenous NKSF/IL-12 to the culture induces differentiation of T helper type 1 (Th1) cells, whereas neutralization of endogenous NKSF/IL-12 with antibodies favors differentiation of Th2 cells. IFN-gamma, a product of Th1 cells, enhances NKSF/IL-12 production by mononuclear cells, whereas IL-10 and IL-4, products of Th2 cells, efficiently inhibit it. Therefore, NKSF/IL-12 appears to be an important inducer of Th1 responses produced by accessory cells during early antigenic stimulation and its production is regulated by a positive feedback mechanism mediated by Th1 cells through IFN-gamma and a negative one by Th2 cells through IL-10 and IL-4. The balance of IL-12 production versus IL-10 and IL-4 production early during an immune response might therefore be instrumental in determining Th1-type versus Th2-type immune responses. Because of this potential role of IL-12 during immune responses, our results demonstrating the impaired ability of HIV seropositive patients to produce NKSF/IL-12 in response to bacterial stimulation suggest that this defect in NKSF/IL-12 production might be a factor contributing to their immune depression.
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PMID:Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammation. 136 96

The influence of cytokines on extracellular superoxide dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
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PMID:Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. 155 78

Lymphocyte activities were determined in a population of 26 institutionalized aged subjects, selected as healthy according to the SENIEUR protocol and previously reported to display immunological and endocrinological abnormalities correlated with depressive disorders. The lymphocyte mitotic response to PHA, which was reduced in aged as compared to adult subjects, was found to be significantly lower and negatively correlated with the depression score in the elderly subjects. In supernatants of PHA-stimulated lymphocyte culture from aged subjects, IL-2, IL-4 and gamma-IFN levels were very low and more severely affected in the depressed aged group. Each cytokine production was negatively correlated with age and depression score. NK activity was lower in the aged and it could be augmented by the addition of IL-2 or alpha-IFN, even though to a lesser extent than in the adult subjects. The nondepressed aged displayed higher levels of IL-2 inducible NK activity than the depressed aged subjects. IL-2 and alpha-IFN stimulated NK activities were negatively correlated with depression score. The present work indicates that the psychological status could affect lymphocyte reactivity in the aged. Given the relatively high frequency of affective disorders in these subjects, the psychological status should be considered in studies of immune senescence.
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PMID:Impairment of lymphocyte activities in depressed aged subjects. 174 61

Short-chain fatty acids are a major by-product of anaerobic metabolism and can be detected in gingival fluid from periodontal pockets. Since most T cells are present subjacent to the pocket epithelium in conjunction with the plasma cells, it is important to know how these T cells are affected by short-chain fatty acids produced by subgingival plaque. The purpose of this study is to examine the effects of extracellular metabolites from periodontopathic bacteria on the proliferation and cytokine production of mouse splenic cells as a potential mechanism of imbalance among host-microbial interactions. A low-molecular-weight, heat-stable agent present in the two-day culture filtrate of Porphyromonas gingivalis, Prevotella loescheii, and Fusobacterium nucleatum significantly depressed Con A- and LPS- induced cell proliferation. To determine whether short-chain fatty acids present in the filtrate could account for the depression, we tested extracted volatile and non-volatile fatty acids for their effects on mitogenic activity. The volatile fatty acids extracted from immunosuppressive supernatants greatly inhibited T- and B- cell proliferation. Among these volatile fatty acids, butyric, propionic, valeric, and isovaleric acids impaired cell proliferation dose-dependently. From gas-liquid chromatographic analysis data, it is suggested that immuno-inhibitory activities in culture filtrates are mainly attributable to butyric and isovaleric acids in P. gingivalis, to propionic, butyric, and isovaleric acids in P. loescheii, and to butyric acid in F. nucleatum. Furthermore, these fatty acids significantly depressed interleukin 2 (IL-2), IL-4, IL-5, IL-6, and IL-10 production by Con A-stimulated splenic-T cells dose-dependently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Volatile fatty acids, metabolic by-products of periodontopathic bacteria, inhibit lymphocyte proliferation and cytokine production. 756 Mar 87

In an attempt to understand better the immunoregulatory disorders in paracoccidioidomycosis (PCM), the possible correlation between interleukin pattern, lymphoproliferation, C-reactive protein (CRP) and specific antibody levels was investigated in the polarized clinical forms of this disease. We studied 16 PCM patients, eight with the disseminated disease (four under treatment and four non-treated) and eight with the chronic disease. The patients with disseminated disease exhibited high antibody titres specific to Paracoccidioides brasiliensis antigen compared with patients with the chronic form of disease. Tumour necrosis factor (TNF), IL-1, IL-6 and CRP in the serum of non-treated disseminated PCM patients were increased, which correlated positively with the low mitogenic response of peripheral blood mononuclear cells (PBMC) to phytohaemagglutinin (PHA) (P < 0.01) and with the high antibody titres (P < 0.001) of these patients. Moreover, we found in the disseminated PCM patients positive correlations between IL-1 and IL-6 (P = 0.0007); IL-1 and TNF (P = 0.0045); IL-1 and IL-6 with the high antibody titres (P = 0.0834 and P = 0.0631, respectively); IL-1, IL-6 and TNF with CRP levels. By contrast, no correlations were found with those interleukins in the treated disseminated and chronic patients or in controls. It was interesting to find an inverse correlation between IL-4 and antibody production in non-treated disseminated PCM (r = -0.4770); moreover, a significant correlation (P = 0.0820) was found in chronic PCM patients with respect to the low level of either IL-4 and antibody titres against fungus antigen. Chronic PCM patients also had IL-2 levels inversely correlated with antibody production (r = -0.6313; P = 0.0628). Inverse correlations were also observed between IL-2 and IL-6 levels in non-treated disseminated patients (P = 0.0501) and between IL-2 and IL-4 in chronic patients (P = 0.0131). The inflammatory cytokines might have a pivotal role in the genesis and in control of some aspects of the disease, such as granulomatous reaction, hypergammaglobulinaemia and depression of T cell-mediated immunity in PCM.
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PMID:Differential correlation between interleukin patterns in disseminated and chronic human paracoccidioidomycosis. 764 15

Acute Plasmodium yoelii murine malaria is associated with a marked depression of splenic T cell responses. The present study was undertaken to address the question if a defect in T cell proliferation results from a relative increase of a non-T cell population in the spleen or real biological changes occurring in T cells of the spleen after infection. When animals were acutely infected, the splenic cells responded poorly to cross-linked anti-CD3 mAb, Con A, and PWM stimulation. At this stage, a very limited array of cytokine was expressed. We failed to detect the transcripts for IL-2R p55, IL-2, IL-6, IL-10, and IFN-gamma in mice with acute P. yoelii malaria irrespective of the number of splenocytes subjected to RT-PCR. In contrast, late in the infection when mice cleared the parasites and became resistant to reinfection, mRNAs for the above cytokines as well as for IL-4, IL-5, GM-CSF, and TNF-alpha were detectable. During this late phase of infection, lymphocytes proliferated vigorously in response to TCR- and T cell mitogen-mediated stimulation. Surprisingly, during an early phase (as early as 3 days postinfection) with low parasitemia, before the establishment of T cell unresponsiveness, a broad array of cytokine expression including IL-2 and IFN-gamma expression as well as marked lymphoproliferative response upon T cell mitogen- and TCR-mediated stimulation was observed. When the expression of cytokine gene in freshly isolated (ex vivo) splenocytes from P. yoelii-infected animals was investigated, a similar pattern of cytokine profile was detected. We devised a methodology in which RNA from an increasing number of splenocytes (ranging from 1 to 16 million) was used to compensate for any difference in the frequency of splenic T cells between immune and acutely infected mice and to augment target molecules which could be measured simultaneously by PCR. The data presented in this study led us to speculate that "anergy" or relative increase of a non-T cell population cannot account solely for the T cell unresponsiveness in the acute phase of infection. We suggest that inactivation or/and ablation of reactive T cells may explain T cell hyporesponsiveness during acute malaria.
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PMID:Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. 784 88

The oral administration of CII by gavage to WA/KIR rats before a conventional arthritogenic challenge with bovine CII in FIA reduced the incidence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell responses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals made less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of peripheral lymph node cells showed that those from tolerized animals expressed less MHC Class II, proliferated less and secreted less IgG2b anti-CII antibody in response to stimulation in vitro with CII when compared with cells from non-tolerant animals. However, this depression of the immune responses to CII seen in vitro was overcome when the cells were incubated with increasing amounts of CII. Tolerance could be transferred to normal animals. Spleen cells, and nylon wool-filtered splenic T cells (but not mesenteric lymph node cells) adoptively transferred hyporesponsiveness to normal recipients which were then less susceptible to collagen-induced arthritis. Transfer of serum from gavaged animals did not modify the susceptibility of normal recipients to arthritis. Spleen cells from gavaged animals suppressed proliferative and antibody responses in co-cultures in vitro with lymph node cells from animals immunized with CII in FIA. The suppressive spleen cell population contained more cells expressing MHC Class II, in both the CD8+ and CD4+ populations. These studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of CII is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.
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PMID:Suppression of collagen induced arthritis by oral administration of type II collagen: changes in immune and arthritic responses mediated by active peripheral suppression. 800 14

Although studies indicate that polymicrobial sepsis produces marked depression in lymphocyte functions, it remains unclear whether this dysfunction is due to the chronic exposure of immune cells to endotoxin (ETX; a product of the gram-negative bacterial cell wall) at levels typically encountered in the septic state. The aim of this study, therefore, was to determine whether the changes in lymphokine release seen during polymicrobial sepsis are comparable to those observed with chronic ETX infusion. To assess this, splenocytes were harvested from C3H/HeN mice (ETX-sensitive) at 1 or 24 hr following cecal ligation and puncture (CLP; to induce polymicrobial sepsis), Sham CLP (Sham), or laparotomy followed by peritoneal implantation of a mini-osmotic pump which delivered either saline vehicle (Sal-pump) or ETX (ETX-pump; 0.025 micrograms lipopolysaccharide/25 g body wt/24 hr). Splenocytes were then stimulated with concanavalin A (2.5 micrograms/ml/48 hr) and their capacity to release interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-10 was determined by bioassay or ELISA. The results indicated that there were no changes in lymphokine release capacity at 1 hr after CLP or ETX-pump implantation. However, prolonged sepsis (i.e., at 24 hr) caused a marked suppression of IL-2 and IFN-gamma release (immune-enhancing lymphokines characteristic of Th1-cells), while enhancing the release of immunosuppressive Th2-cell products IL-4 and IL-10. Chronic exposure to ETX at a level comparable to that seen in CLP caused no depression in lymphokine (IL-2/IFN-gamma) release. This implies that a bacterial component other than ETX mediates the differential alterations observed in lymphokine release during prolonged polymicrobial sepsis.
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PMID:Polymicrobial sepsis but not low-dose endotoxin infusion causes decreased splenocyte IL-2/IFN-gamma release while increasing IL-4/IL-10 production. 801 14

Visceral leishmaniasis is associated with a marked depression of T cell responses, which has been characterized by the absence of IL-2 and IFN-gamma production by lymphocytes on in vitro stimulation with Leishmania Ag. The aim of this study was to evaluate both the mechanism of these immunologic abnormalities and the restoration of in vitro T cell responses to Leishmania Ags. A total of 15 untreated visceral leishmaniasis patients were evaluated. Although IFN-gamma and IL-4 levels in the supernatants of lymphocyte cultures were very low or absent, mRNA for these cytokines and for IL-10 were observed in PBMCs. Addition of IFN-gamma plus IL-2 enhanced lymphocyte proliferation by 158%. Restoration of T cell proliferative responses and IFN-gamma production was also observed by the addition of a neutralizing mAb alpha-IL-10. Neutralizing mAb alpha-IL-4 did not restore T cell responses but alpha-IL-10 and alpha-IL-4 mAbs had a synergistic effect on lymphocyte proliferation. The IFN-gamma levels in supernatants of lymphocyte cultures stimulated with Leishmania chagasi Ag or L. chagasi Ag plus alpha-IL-4, alpha-IL-10, or alpha-IL-4 plus alpha-IL-10 mAbs were 26 +/- 30 pg/ml, 41 +/- 18 pg/ml, 146 +/- 73 pg/ml, and 174 +/- 106 pg/ml, respectively. These data indicate that Th2 cell activation occurs in visceral leishmaniasis and that in vitro production of IFN-gamma and lymphocyte proliferation can be restored by blocking the inhibitory effect of the Th2 cytokines on mononuclear cells.
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PMID:Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis. 820 20


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