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)

Cytokine production was previously demonstrated to be reduced in untreated major affective patients. In addition, recovery from depression following clomipramine (CMI) treatment was accompanied by the restoration of interleukin-1 beta (IL-1 beta) and interleukin-3-like activity (IL-3-LA) to normal range. In the present study we assessed the in vitro production of IL-1 beta IL-2, and IL-3-LA by peripheral blood mononuclear cells (PBMC) in 11 nondepressed patients with obsessive compulsive disorder (OCD) before and after 8 weeks of CMI treatment. Results were compared with those of 11 healthy subjects. CMI treatment induced a significant improvement in OCD symptoms. No alteration was observed in cytokine production in OCD patients before treatment as compared to control subjects. Moreover, 8 weeks of drug treatment had no effect on cytokine production. In conclusion, OCD per se, as well as CMI treatment, have no effect on interleukin production as measured in this study.
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PMID:Cytokine production in obsessive-compulsive disorder. 942 92

Shock and multiple organ failure are complications of primary conditions such as trauma, hemorrhage and infection. Ample evidence of cardiac contractile dysfunction has been obtained in both septic patients and experimental animal models of endotoxin shock. Recent advance in molecular biology and immunology has improved our understanding of the pathogenesis of septic shock, and thus, it is now believed that the host's inflammatory response to infection contributes to the development of septic shock. In addition, effects of toxic host mediators including cytokines, kinins, eicosanoids, platelet-activating factor, and nitric oxide, which are produced by activated cells, on cardiovascular system have been examined. The possible involvement of the nitric oxide pathway, not only as a marker for cytokine-induced effects on myocyte gene expression, but also as a mediator for cytokine-induced contractile dysfunction, was explored. According to this hypothesis, trauma and hemorrhage, both of which lead to host's inflammatory response, is also considered to induce contractile dysfunction. In this paper we reviewed the influences of various shock states on cardiac contractility. Hemorrhagic and burn shocks possibly depress cardiac contractility as well as septic and endotoxin shocks. Therefore, it is necessary to improve contractile depression in the diseased states to meet oxygen demand of each patient under monitoring patient's circulatory and metabolic conditions.
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PMID:[Cardiac contractile dysfunction in response to surgical stress including trauma, hemorrhage, and infection]. 894 Jun 86

Leishmania are parasites that survive within macrophages by mechanism(s) not entirely known. Depression of cellular immunity and diminished production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha are potential ways by which the parasite survives within macrophages. We examined the mechanism(s) by which lipophosphoglycan (LPG), a major glycolipid of Leishmania, perturbs cytokine gene expression. LPG treatment of THP-1 monocytes suppressed endotoxin induction of IL-1 beta steady-state mRNA by greater than 90%, while having no effect on the expression of a control gene. The addition of LPG 2 h before or 2 h after endotoxin challenge significantly suppressed steady-state IL-1 beta mRNA by 90% and 70%, respectively. LPG also inhibited tumor necrosis factor alpha and Staphylococcus induction of IL-1 beta gene expression. The inhibitory effect of LPG is agonist-specific because LPG did not suppress the induction of IL-1 beta mRNA by phorbol 12-myristate 13-acetate. A unique DNA sequence located within the -310 to -57 nucleotide region of the IL-1 beta promoter was found to mediate LPG's inhibitory activity. The requirement for the -310 to -57 promoter gene sequence for LPG's effect is demonstrated by the abrogation of LPG's inhibitory activity by truncation or deletion of the -310 to -57 promoter gene sequence. Furthermore, the minimal IL-1 beta promoter (positions -310 to +15) mediated LPG's inhibitory activity with dose and kinetic profiles that were similar to LPG's suppression of steady-state IL-1 beta mRNA. These findings delineated a promoter gene sequence that responds to LPG to act as a "gene silencer", a function, to our knowledge, not previously described. LPG's inhibitory activity for several mediators of inflammation and the persistence of significant inhibitory activity 2 h after endotoxin challenge suggest that LPG has therapeutic potential and may be exploited for therapy of sepsis, acute respiratory distress syndrome, and autoimmune diseases.
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PMID:Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1 beta gene expression in human monocytes via a unique promoter sequence. 896 19

In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1 beta), and plasma tumor necrosis factor-alpha (TNF-alpha) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 age-matched control subjects (C). AD patients showed higher concentrations of histamine (AD = 452.9 +/- 237.9 pmol/mL; C = 275.3 +/- 151.5 pmol/mL; p < 0.05) and IL-1 beta (AD = 211.2 +/- 31.1 pg/mL; C = 183.4 +/- 24.4 pg/mL; p < 0.01), and lower values of TNF-alpha (AD = 3.59 +/- 2.02 pg/mL; C = 9.47 +/- 2.64 pg/mL; p < 0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-alpha were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1 beta values compared with age-matched controls. Age negatively correlated with histamine (r = -0.57; p < 0.05) and positively with IL-1 beta levels (r = 0.48; p < 0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-alpha scores and age was only found in AD patients (r = 0.46; p < 0.05). Furthermore, histamine and TNF-alpha values correlated negatively in AD (r = -0.50, p < 0.05). In addition, cognitive impairment increased in patients with lower TNF-alpha and higher histamine and IL-1 beta levels, as indicated by the correlations between mental performance scores and histamine (r = -0.37, ns), IL-1 beta (r = -0.33, ns) and TNF-alpha levels (r = 0.42, p < 0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r = -0.63, p < 0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.
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PMID:Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. 897 99

To investigate the role of the hypothalamic-pituitary-adrenal (HPA) axis in behavioral responses to infection, we studied the effects of corticosterone on depressed social behavior induced by peripheral and central interleukin-1 beta (IL-1 beta) in the rat. Intact and adrenalectomized (ADX) rats were injected i.p. with IL-1 beta (500 ng) and their motivation to investigate a juvenile conspecific was assessed. Whereas ADX rats showed a marked depression in social behavior following i.p. IL-1 beta, intact controls did not. To verify that corticosterone was responsible for inhibiting the effects of IL-1 beta, corticosterone pellets or placebos were implanted i.p. in ADX rats. Following i.p. injection of IL-1 beta, ADX rats with placebos experienced depressed social behavior. Corticosterone replacement, however, reversed this effect in ADX rats, confirming that corticosterone modulates the behavioral effects of peripheral IL-1 beta. To determine if corticosterone modulates sickness behavior directly in the CNS, intact and ADX rats were injected i.c.v. with IL-1 beta or lipopolysaccharide (LPS). Although centrally administered IL-1 beta depressed social behavior to a similar extent in intact and ADX rats, the depression was prolonged in ADX rats. However, social behavior of ADX rats injected i.c.v. with LPS was depressed more than in intact controls, and this effect was reversible by corticosterone replacement. These results are interpreted to indicate that corticosterone inhibits the behavioral effects of IL-1 beta in the periphery and, perhaps, in the CNS. That the behavioral effects of central LPS were inhibited by corticosterone suggests the HPA axis may modulate behavior by regulating cytokine synthesis in the CNS.
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PMID:Role of corticosterone in the behavioral effects of central interleukin-1 beta. 897 27

CD4-targeted therapy with a nondepleting RIB-5/2 mAb abrogates accelerated (< 36 h) rejection in presensitized LEW rats and results in permanent acceptance of LBNF1 cardiac allografts in conjunction with the features of infectious tolerance. This study examined the role and functional significance of the Th1 and Th2 cytokine network and systemic host allospecific Ab (allo-Ab) responses in the development of the infectious tolerance pathway in this model. Long term survival of cardiac transplants in rats treated with the tolerizing RIB-5/2 mAb regimen was accompanied by profound depression of Th1 (IL-2 and IFN-gamma) and Th2 (IL-4, IL-10) cytokines at the graft site, as shown by competitive template reverse transcription-PCR and immunohistochemistry. In contrast, the expression of Th2-type cytokines was selectively up-regulated after transfer of infectious tolerance by spleen cells into new generations of primary and secondary test recipients. Donor-specific circulating IgM allo-Ab responses were diminished throughout, and the switch from IgM to IgG allo-Ab was completely prevented in tolerant hosts, as shown by flow cytometry. The demonstration that treatment with cytolytic anti-CD4, but not anti-CD8, mAb recreated rejection of test cardiac allografts with simultaneous down-regulation of IL-4 mRNA/protein expression underlines the importance of this cytokine in the development of infectious tolerance. Hence, this report documents distinct cytokine elaboration patterns in animals tolerized by CD4-targeted therapy compared with those rendered tolerant by putative regulatory Th2-like cells. The mechanism of tolerance in anti-CD4 mAb-treated hosts appears distinct from that operating in the absence of mAb, when the tolerant state is being transferred in an infectious manner to new cohorts of test recipients.
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PMID:Type 2 helper T cell-type cytokines and the development of "infectious" tolerance in rat cardiac allograft recipients. 902 92

T lymphocytes from tumor-draining lymph nodes (TDLN), after activation and expansion in vitro, can mediate regression of metastatic tumor in animal models. We have shown that TDLNs are subject to tumor-induced suppression that is tumor specific, T-cell mediated, and dependent on the duration of tumor growth, but the mechanism of this suppression remains largely unknown. Recently, in other model systems, tumor-bearer T cells have been shown to have decreased expression of T-cell receptor-zeta (TCR zeta), a key component in antigen-driven activation pathways. We sought to investigate whether the suppression of TDLN reactivity that accompanies prolonged tumor growth was associated with decreased expression of TCR zeta in fresh and in vitro activated lymph node lymphocytes. Mice bearing subcutaneous tumor deposits of MCA 205 had TDLN cells harvested after various durations of tumor growth, then activated in vitro with anti-CD3 for 2 days (activation phase), followed by expansion with interleukin-2 (IL-2) (10 U/ml) for 3 days (expansion phase). Two-color flow cytometry was used to determine TCR zeta expression in fresh and activated TDLN cells. Antitumor reactivity was assessed by the ability of activated TDLN to mediate regression of lung metastases. There was a time-dependent suppression of the antitumor reactivity of the activated TDLN; activated TDLN from mice bearing tumors 14 days or less were able to mediate the regression of established lung metastases, whereas activated TDLN from animals bearing tumors 21 days or more were ineffective. In addition, TCR zeta expression on T lymphocytes from fresh and activated TDLN was also depressed in a time-dependent manner. Because tumor-induced immunosuppression in our model is known to be T cell mediated, we examined whether the Th2 cytokine IL-4, when added in vitro during activation or expansion, could suppress antitumor reactivity and lead to a depression in TCR zeta expression of TDLN cells in a fashion similar to prolonged tumor growth. The addition of 10 U/ml of IL-4 in vitro had a marked suppressive effect on the antitumor activity of day 14 TDLN; the effect was most pronounced when IL-4 was present during the expansion phase. Fluorescence-activated cell sorter analysis of day 14 TDLN exposed to IL-4 in vitro demonstrated a marked decrease in TCR zeta expression, comparable to that seen in late tumor-bearer TDLN. Thus, TDLN from late tumor-bearers show a consistent decrease in TCR zeta expression that is associated with suppressed antitumor reactivity, and exposure to IL-4 in vitro results in qualitatively and quantitatively similar changes. Our observations suggest a mechanism whereby Th2 cells could mediate immunosuppression by downregulating a critical component of the T-cell-receptor signal transduction machinery.
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PMID:Tumor-induced suppression of antitumor reactivity and depression of TCRzeta expression in tumor-draining lymph node lymphocytes: possible relationship to the Th2 pathway. 908 83

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.
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PMID:Inotropic agents in the treatment of heart failure: despair or hope? 911 Jan 13

There is a strong interrelationship between the immune system, the central nervous system and psychological processes that are suggested to play a pivotal role in the pathogenesis of psychiatric disorders. In schizophrenia and depression, activation of the immune system has been observed repeatedly. Cytokines play a key role in immune activation. They are actively transported into the CNS, but also released from activated glia cells. Cytokines activate glia cells in the CNS to produce other cytokines, and a cascade of cytokine effects may be initiated by this mechanisms. During the past few years, the influence of the cytokines on dopaminergic, noradrenergic and serotonergic neurotransmission and also on the hormones of the hypothalamus-pituitary-adrenal axis has been elucidated. It suggests a pivotal role in psychological processes and psychiatric disorders. For example, in schizophrenia the IL-2 cerebrospinal fluid concentration shows a stronger relationship to the relapse probability than catecholamine metabolites. Although the hypersecretion of IL-2 in schizophrenia and of IL-6 in depression are suggested to play key roles for these disorders, a specificity of certain cytokines for certain psychiatric disorders seems unlikely. Psychomotor, sleep and sickness behavior are influenced by IL-1, disturbances of memory and attention by IL-2, but also by TNF-alpha. From the distribution of cytokine receptors in the CNS conclusions can be drawn regarding the influence of cytokines on psychological processes. The finding that norepinephrine stimulates activated astrocytes to produce IL-6 implies that the cytokine cascade may be activated by neuronal processes under certain conditions. This can lead to a molecular biological explanation of the influences of stress on the immune system. Lastly, influences of the cytokines on blood-brain barrier disturbances and further consequences resulting from the role of the cytokine network in the CNS are discussed.
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PMID:[Role of the cytokine network in the CNS and psychiatric disorders]. 913 17

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432-inducible cytokine production (interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha) at baseline. Treatment with OK-432 reversed this deficit for interferon gamma (IFN gamma) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients with resected melanoma.
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PMID:Phase IB trial of picibanil (OK-432) as an immunomodulator in patients with resected high-risk melanoma. 919 73


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