Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation.The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1&#946; , soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)- &#945; in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy.Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays.According to our results, serum IL-1&#946; , sIL-2R, IL-6, IL-8 and TNF-&#945; concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-&#945; concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients.The present study demonstrates that plasma levels of IL-1&#946; , sIL-2R, IL-6, IL-8 and TNF-&#945; adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-&#945; may contribute to symptomatology in schizophrenia.

Ay&#351;e Binnur Erba&#287;ci

Hasan  Herken

Oya  K&#246;yl&#252;oglu

Necat  Yilmaz

Mehmet  Tarak&#231;ioglu

Serum IL-1&#946;, sIL-2R, IL-6, IL-8 and TNF-&#945; in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment

Background: Human peripheral blood mononuclear cells (PBMC) left in microcultures for 24 h without mitogen do not respond to subsequent stimulation with PHA. They regain reactivity if the native culture medium is absorbed with other party lymphocytes or partially replaced with the medium from a PHA-stimulated culture. The observations suggest that, during the incubation, some inhibitory agent had accumulated in the culture medium.Aim: The study was performed to determine the nature of the observed phenomenon in respect of the possible role of monocytes and their products IL-1 and IL-1 receptor antagonist (IL-1ra), and to test for immunodiagnostic purposes the significance of quantifying the lymphocyte response to delayed stimulation with PHA in patients suffering from inflammatory prosesses.Methods: Lymphocyte response to delayed stimulation with PHA, calculated as the lymphocyte-monokine interaction (LM) index, was determined in the microcultures of PBMC isolated from the blood of healthy donors or of patients with acute tonsilitis. The values of LM indices were compared with the ratios of IL-1ra/IL-1&#946; concentration estimated by enzyme-linked immunosorbent assay method in the culture supernatants. The influences of exogenous IL-1&#946; , IL-1ra, anti-IL1ra antibodies and antibiotic cefaclor on the monokine concentrations and on the values of LM index were tested.Results and conclusions: The results show that the level of lymphocyte response to delayed stimulation with PHA (LM index) is inversely proportional to the ratio of IL-1ra/IL-1&#946; concentration in the culture. The low LM values at high IL-1ra/IL-1&#946; ratios in PBMC cultures from healthy donors, reversed proportions found in patients' PBMC (acute tonsilitis), and the cefaclor-induced reduction of LM value with correlated increase of the IL-1ra/IL-1&#946; ratio suggest that the LM assay may prove to be useful for immunodiagnostic purposes.

Marek P. D&#261;browski

Wanda  Stankiewicz

Tadeusz  P&#322;usa

Andrzej  Chcia&#322;owski

Stanis&#322;aw  Szmigielski

Competition of IL-1 and IL-1ra determines lymphocyte response to delayed stimulation with PHA

Background: Isoferulic acid (IFA) is a main active ingredient of the rhizoma of Cimicifuga heracleifolia, which is used frequently in Japanese traditional medicine as an anti-inflammatory drug. It has been revealed that IFA inhibits the production of macrophage inflammatory protein-2 (MIP-2), which is a murine counterpart of the chemokine family that may contribute to the pathogenesis of inflammatory diseases through the chemotactic activity for inflammatory and immune effector cells.Aim of the study: In this study, we investigated the therapeutic effect of IFA on the progression of lethal influenza virus pneumonia in mice by comparison with that of dexamethasone (DX), a potent inhibitor for various inflammatory cytokines including MIP-2.Methods: Mice were infected by intranasal inoculation of influenza virus under ether anesthesia. The IFA or DX was given by oral administration once daily for 4 days after infection. After infection, the survival rate and the change in body weight were daily monitored.Results: IFA administration markedly improved the survival rate and body weight loss of influenza virusinfected mice in a suitable dose range (0.5 mg/day). However, DX administration did not show a beneficial effect at any dose.Conclusion: These data suggested that IFA is a novel tool not only for the intervention therapy, but also for the studies on the pathogenesis of influenza virusinduced pneumonia.

Shinya Sakai

Hiroshi Ochiai

Naoki Mantani

Toshiaki Kogure

Naotoshi Shibahara

Katsutoshi Terasawa

Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice

Two {Met(0)6}deacetyl-thymosin &#x3B2;4 analogs containing Phe(4F) or Tyr(Me) at position 12 were synthesized by the manual solid-phase method, and their anti-inflammatory effect on carrageenin-induced edema in the mouse paw was studied. Fluorination of the para-position of Phe12 resulted in a marked antiinflammatory effect on carrageenin-induced edema in the mouse paw compared with that of our synthetic {Met(0)6}deacetyl-thymosin &#x3B2;4, but the other analog, 
{Met(0)6, Tyr(Me)12}deacetyl-thymosin &#x3B2;4, showed 
a marked reduction of the anti-inflammatory effect.

T. Abiko

R. Ogawa

Syntheses of two deacetyl-thymosin &#x3B2;4 analogs and their anti-inflammatory effect on carrageenin-induced edema in the mouse paw

Background: The preventive effect of low-dose aspirin in cardiovascular disease is generally attributed to its antiplatelet action caused by differential inhibition of platelet cyclooxygenase-1. However, there is evidence that aspirin also affects release of inflammatory cytokines, including tumor necrosis factor-&#945; (TNF-&#945;). It is not known whether this is caused by direct action on the cytokine pathway or indirectly through cyclooxygenase inhibition and altered prostanoid synthesis, or both.Methods: We assessed the capacity of lipopolysaccharide-activated leukocytes in whole blood cultures of eight healthy subjects following a single oral dose of 80 mg aspirin to release TNF-&#945;, prostanoid E2 
(PGE2) and prostanoid I2 (PGI2), and thromboxane A2 (TXA2). TNF-&#945; and prostanoids were determined by enzyme-linked immunoassays.Results: In seven subjects, TNF-&#945; release in blood cultures decreased 24 h after intake of aspirin. The effect of aspirin on prostanoid release was assessed in three individuals: PGE2 increased in all subjects, 
PGI2 increased in two and remained unchanged in one, and TXA2 was reduced in two and unchanged in one individua2l. The presence of DFU, a specific inhibitor of cyclooxygenase 2, did not affect the reduction of TNF-&#945; release by aspirin, but abolished prostanoid production in all three individuals.Conclusion: The capacity of activated leukocytes to release TNF-&#945; is reduced by ingestion of low-dose aspirin, independent of changes in prostanoid biosynthesis.

Ilse  Beckmann

Shlomo  Ben-Efraim

Monica  Vervoort

Henk C. S. Wallenburg

Release of tumor necrosis factor-&#945; and prostanoids in whole blood cultures after 
in vivo exposure to low-dose aspirin

Background: Endometriosis is defined as an inflammatory condition of the female reproductive tract, a state often associated with infertility and miscarriage. Many exogenously administered factors (treatments) control the disease via as yet unknown pathways. Possible candidate molecules involved in these mechanisms could be the serum-soluble human leukocyte antigens (sHLA) that have been detected in a variety of human body fluids and that are associated with several diseases.Aims: We here examine how danazol and leuprorelin acetate depot treatments exert their anti-inflammatory action. It is plausible that subtle alterations mediated by these treatments and in relation to sHLA may explain the pathophysiology of endometriosis and provide insights towards new therapeutic protocols.Methods: Indirect enzyme-linked immunosorbent assay (ELISA), using specific monoclonal antibodies, determined serum-soluble class-I and class-II HLA levels. ELISA readings from treated women were compared with normal healthy subjects.Results: Serum-soluble class-I and class-II HLA levels are statistically significantly lower 
(<mml:math alttext="$P &#60; 0.001$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.001</mml:mn></mml:mrow></mml:math>) in women with endometriosis than in the control groups. However, danazol but not leuprorelin acetate depot administration augments soluble HLA class I and class II (<mml:math alttext="$P &#60; 0.01$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.01</mml:mn></mml:mrow></mml:math>
 and <mml:math alttext="$P &#60; 0.001$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.001</mml:mn></mml:mrow></mml:math>, respectively) to normal levels during the treatment period, an increase that may account for the anti-inflammatory effect and the remission observed.Conlusions: It is shown that one of the underlying causes of endometriosis may be the lack of both circulating class-I and class-II antigen levels. Danazol administration acts via an induced release of these antigens, whose presence correlates with the degree of the inflammatory alleviation obtained. We thus provide evidence that the inflammatory state of the disease appears to be associated with soluble HLA levels because, 3 months after ceasing therapy, the circulating antigens in the serum return to the same levels that correspond to the pathological condition.

Ioannis M. Matalliotakis

Irene  Athanassakis

Anastasia G. Goumenou

Maria A. Neonaki

Emmanuil E. Koumantakis

Simon  Vassiliadis

Evgenios E. Koumantakis

The possible anti-inflammatory role of circulating human leukocyte antigen levels in women with endometriosis after treatment with danazol and leuprorelin acetate depot

Background: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD), and measurement of NO metabolites may be useful for monitoring disease activity.Aims and objectives: To characterise urinary nitrite levels, a stable metabolite of NO, in IBD and to evaluate its potential as a marker of disease activity.Methods: Twelve-hour urinary nitrites were measured by the microplate assay method in 46 patients with IBD (active; n = 32). Urinary samples from 16 healthy individuals served as controls.Results: Increased levels of urinary nitrites were found in patients with active IBD compared with those with inactive IBD. Twenty-eight out of 32 patients (87.5%) with active IBD had detectable levels of nitrite in their urine as compared with 2/14 (14.3%) patients with inactive IBD. None of the 16 healthy controls had detectable urinary nitrite. Twelve-hour urinary nitrite in active compared with inactive IBD: 5 &#298; 0.7 versus 0.1 &#298; 0.04 &#956; mol 
<mml:math alttext="$\left( {P &#60; 0.05} \right)$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.05</mml:mn></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:math>. There was good correlation between urinary nitrite and some markers of disease activity in IBD such as C-reactive protein and microalbuminuria but not with erythrocyte sedimentation rate.Conclusions: Increased levels of nitrite were detected in urine of patients with active IBD, consistent with increased NO synthesis. This simple assay may be exploited as a potential marker of disease 
activity in IBD.

Michael G. Goggins

Syed A. Shah

Jason  Goh

Anil  Cherukuri

Donal G. Weir

Dermot  Kelleher

Nasir  Mahmud

Increased urinary nitrite, a marker of nitric oxide, in active inflammatory bowel disease

Background: The life expectancy of patients with cystic fibrosis (CF) is largely dependent on the pulmonary disease severity and progress. Malnutrition may be an important complicating factor in active and chronic lung disease.Aims: The focus of this study was to investigate several inflammatory markers in pancreatic-insufficient CF patients with different enzyme treatment regimens.Methods: CF patients with pancreatic insufficiency were examined at a time of symptomatic exacerbation of their lung disease. Group A (n = 11) regularly received microspheric enzymes. Group B (n = 8) were treated with enzymes during the hospitalization period only and demonstrated the presence of malnutrition. Inflammatory markers in the sputa (neutrophil elastase activity, interleukin-8 and tumour necrosis factor-α levels) and in the peripheral blood (plasma malondialdehyde (MDA), lymphocyte response to PHA, and the cell sensitivity to steroid suppression) have been investigated.Results: During acute lung exacerbation, group B demonstrated reduced levels of lymphocyte proliferation. This parameter was normalized after combined antibiotic and pancreatic enzyme therapy. Simultaneously, plasma MDA in group B markedly increased following treatment. For this group, a significant positive linear association between values of plasma MDA and lymphocyte proliferation has been observed. For group A, neither the same correlation nor changes in MDA levels and lymphocyte proliferation have been found.Conclusions: Our data indicate that acute lung exacerbation in malnourished CF patients may be associated with alteration in T-lymphocyte activity. Adequate therapy normalizes lymphocyte function but results in systemic oxidative stress.

Galina V. Shmarina

Alexander L. Pukhalsky

Svetlana N. Kokarovtseva

Daria A. Pukhalskaya

Elena A. Kalashnikova

Nikolaï I. Kapranov

Natalia J. Kashirskaja

Improvement of nutrient absorption may enhance systemic oxidative stress in cystic fibrosis patients

Freek J. Zijlstra

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Mediators of Inflammation publishes papers on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell adhesion-promoting molecules

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Chief Editor, Professor Agrawal, is an Assistant Clinical Professor of the Division of Basic and Clinical Immunology. Dr. Agrawal's research focuses on the dendritic cells of the immune system in the context of aging and autoimmunity.

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Mediators of Inflammation - Table of contents 2001

title

Mediators of Inflammation publishes papers on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell adhesion-promoting molecules

Mediators of Inflammation