Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis.

The aim of our study was to evaluate the role of proinflammatory cytokines: tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), as well as the possible contribution of interleukin-10 (IL-10) in anemia of chronic disease (ACD) of rheumatoid arthritis (RA) patients. We measured the serum levels of TNFalpha, IL-1beta, and IL-6 in 105 anemic and 127 nonanemic RA patients. We also investigated the effects of the above cytokines on the development of burst-forming units-erythroid (BFUe) and colony-forming units-erythroid (CFUe) in bone marrow cultures. Anemic patients had significantly higher serum levels of TNFalpha, IL-1beta, and IL-6 compared to nonanemics. Serum IL-10 levels were low and there was no significant difference in IL-10 concentrations between anemic and nonanemic patients. Proinflammatory cytokines inhibited proliferation of BFUe and CFUe. IL-10 did not decrease the erythroid colony growth. Proinflammatory cytokines may play a role in the pathogenesis of ACD in RA patients. Low levels of IL-10 possibly contribute to the development of ACD.     

Cytokine levels in midtrimester amniotic fluid in normal pregnancy and in the prediction of pre-eclampsia

Midtrimester amniotic fluid cytokines may reflect the function of the maternal immune system in the maternal-fetal interface and thus be predictive of pre-eclampsia. We determined the concentrations of interleukin (IL)-6, IL-8, IL-10, IL-11, IL-12, IL-15, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta in amniotic fluid at 14-16 weeks of gestation from women with normal pregnancies and from those who subsequently developed severe pre-eclampsia. The concentrations of the cytokines in amniotic fluid did not significantly differ between patients and normal controls. The median concentration of IL-6 was 950 pg/ml in normal pregnant women and 578 pg/ml in the patient group. The median concentration of IL-8 was 606 pg/ml in normal controls and 294 pg/ml in the patient group. The levels of IL-6, IL-8 and TGF-beta correlated positively with each other. TNF-alpha concentrations were low and similar in both groups. IL-10 and IL-12 were detected at very low levels in 37 and 7% of the samples, respectively. No difference was found in IL-15 concentrations between the groups. IL-11 was found only at low levels in both groups. Although none of the cytokines measured was predictive of pre-eclampsia, this study provides information of cytokines in amniotic fluid during the period when the spiral arteries are remodelled.     

Concentration of fetal plasma and amniotic fluid interleukin-1 in pregnancies complicated by preterm prelabour amniorrhexis.

AIMS--To determine interleukin-1 beta (IL-1 beta) concentration in fetal and maternal plasma and amniotic fluid from pregnancies complicated by preterm prelabour amniorrhexis and to define the relation of this cytokine to intrauterine infection and the onset of labour. METHODS--Cross-sectional study of 23 pregnancies complicated by preterm prelabour amniorrhexis. Enzyme linked immunoassay was used to measure IL-1 beta concentration in fetal and maternal plasma and amniotic fluid. In each case, fetal blood and amniotic fluid were cultured for micro-organisms. RESULTS--In pregnancies with positive fetal blood and/or amniotic fluid cultures, plasma and amniotic fluid concentrations of IL-1 beta were higher and the interval between amniorrhexis and onset of labour was shorter than in the non-infected group. There were no significant associations between fetal plasma IL-1 beta and maternal plasma or amniotic fluid IL-1 beta concentrations, fetal leucocyte count or the interval between amniorrhexis and the onset of labour. CONCLUSIONS--These findings suggest that although intrauterine infection is associated with increased IL-1 beta concentrations in fetal plasma and amniotic fluid, there is no significant association between the concentration of IL-1 beta and the interval between amniorrhexis and the onset of labour.     

Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition.

Interleukin-1 (IL-1) has been implicated in the mechanism of human parturition in the setting of infection. The purpose of this study was to determine the effect of labor (term and preterm) and microbial invasion of the amniotic cavity on amniotic fluid (AF) concentrations IL-1 alpha and IL-1 beta. AF was retrieved by transabdominal amniocentesis from the following groups of women: midtrimester genetic amniocentesis (16 to 18 wk) (N = 15), preterm labor with intact membranes (21 to 36 wk) with or without infection (N = 72), preterm premature rupture of membranes (PROM) (N = 88), and term not in labor or in active labor with or without infection (N = 58). AF was cultured for aerobic and anaerobic bacteria as well as Mycoplasmas. IL-1 was measured with a commercially available immunoassay validated for AF (sensitivity: IL-1 alpha, 157 pg/ml; IL-1 beta, 50 pg/ml). All women at midtrimester had undetectable AF IL-1 alpha and IL-1 beta. Among women in preterm labor with positive AF cultures, IL-1 alpha and IL-1 beta were detectable in the AF in 86.6% (13/15) and 100% (15/15), respectively. In contrast, all women with negative AF cultures without labor (N = 36) had undetectable AF IL-1 alpha concentrations and 52.7% (19/36) had undetectable AF IL-1 beta concentrations. Histopathological chorioamnionitis was present in 92.8% (13/14) of patients who had positive AF cultures and detectable IL-1 in the AF. IL-1 was significantly higher in patients with preterm PROM, labor, and positive AF cultures than in the other subgroups of patients with preterm PROM.(ABSTRACT TRUNCATED AT 250 WORDS)     

An Interleukin-23 Binding Protein in Mid-Trimester Amniotic Fluid

Problem  The binding of mid-trimester amniotic fluid to cytokines was evaluated.
Method of study  Purified tumor necrosis factor-α (TNF-α), interleukin (IL)-10, IL-12, and IL-23 were incubated with amniotic fluid from 25 women undergoing a mid-trimester amniocentesis, or with bovine serum albumin or saline, and cytokine binding to monoclonal antibodies was quantitated by ELISA. Aliquots of amniotic fluid were heated to 95°C for 15 min and then retested for IL-23 binding. The effect of amniotic fluid dilution on IL-23 quantitation was evaluated.
Results  All amniotic fluids had a negligible effect on TNF-α, IL-10, and IL-12 detection. In marked contrast, pre-incubation with amniotic fluid from each subject reduced the subsequent ability to detect IL-23 by >50%. The extent of inhibition was directly proportional to the amniotic fluid dilution and was markedly reduced following heating at 95°C for 15 min. Amniotic fluids from White, Black, Asian, East Indian, and Hispanic women were equally effective.
Conclusion  Interleukin-23 and IL-12 share a common p40 subunit and no inhibition of IL-12 was apparent. It appeared that a component of mid-trimester amniotic fluid specifically interacts with the p19 subunit unique to IL-23. Mid-trimester amniotic fluid reactivity with IL-23 may be a mechanism to limit intra-amniotic neutrophil-derived inflammation.     

Maternal serum alpha-fetoprotein and fetal trisomy-21 in women 35 years and older: implications for alpha-fetoprotein screening programs

A retrospective study of 3,411 women who underwent midtrimester amniocentesis for fetal chromosome analysis between June 1979 and August 1984 was performed to evaluate an association between low maternal serum alpha-fetoprotein (AFP) concentrations and Down syndrome (DS) pregnancies. A total of 71 pregnancies was found with abnormal fetal chromosomes; of these, 26 cases were trisomy-21 and 10 cases were trisomy-18. The maternal serum AFP in women with DS fetuses was relatively lower than levels in women with fetuses that had normal chromosomes. In addition, the AFP concentrations in amniotic fluid were decreased in cases involving DS fetuses. We have estimated the risks for DS pregnancy at all maternal ages and most serum AFP concentrations. Using these calculations, genetic counselors will be able to provide more accurate risk estimates for trisomy-21 following maternal serum AFP testing.     

Cervical cytokine responses in women with primary or recurrent chlamydial infection.

Little is known about concurrent expression of cervical cytokines and their regulation by sex hormones during primary or recurrent chlamydial infections in humans. Cytokine (interleukin-1beta [IL-1beta], IL-6, IL-10, interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha]) concentrations in cervical washes and serum samples, along with levels of beta-estradiol and progesterone in women with primary or recurrent chlamydial infections and healthy controls, were measured by ELISA. Women with recurrent infections had significantly higher levels of IFN-gamma in cervical washes than did women with primary infections. Significant negative correlation was found between IL-1beta and progesterone levels during recurrent infections. Beta-estradiol levels in women with primary infections showed significant negative correlations with cervical concentrations of IL-10, IL-1beta, and IL-6. Our study suggests that Chlamydia trachomatis infection in the female genital tract may be regulated by both the synergistic actions of the cytokines and the sex hormones beta-estradiol and progesterone.     

Antenatal diagnosis of argininosuccinic aciduria

Argininosuccinic aciduria (ASAuria) is an inherited disorder of ureogensis characterized by periodic hyperammonemia, seizures, and mental retardation. Transabdominal amniocentesis was performed at 16 weeks' gestation on a 31-year-old female whose one previous child had this disease. ASA concentration in the amniotic fluid was 0.073 μmoles/ml (normal = 0). Cultured amniotic cells incubated with L-citrulline-ureido-¹¹C accumulated ASA-¹⁴C as did cultured fibroblasts of patients with ASAuria; normal cells (including those from subjects heterozygous for argininosuc-cinasc deficiency) do not accumulate this metabolic intermediate.
Pregnancy was terminated at 22 weeks by hysterotomy. Fetal liver ASase was 3–5 percent of normal, and liver ASA concentration was 9.36 μmoles/g wet wt. (normal = 0), confirming the prediction of an affected fetus. Fetal cord serum ASA and citrulline concentrations were 0.098 and 0.071 μmoles/ml, respectively; simultaneous maternal concentrations were 0 and 0.014. Maternal urine ASA concentrations during pregnancy were 0.15.5 and 0.166 μmoles/mg crmtinine; 10 weeks after tcrmination, ASA was present in only trace amounts.
Current emphasis is on development of techniques to minimize the delay between amniocentesis and intrauterine diagnosis. It is possible that this and some other no-threshold aminoacidurias may be diagnosed on the basis of amniotic fluid amino acids alone.     

Beta-2 mimetics and magnesium: true or false friends?

Physiological beta stimulation may be involved in the regulation of magnesium status namely by homeostatic increase of magnesemia during magnesium deficiency. But conversely excessive beta stimulation namely by use of pharmacological high doses of beta mimetics may induce a decrease of magnesemia. Two different types of magnesium therapy ought to be distinguished. Nutritional magnesium therapy which may physiologically palliate a magnesium deficiency due to an insufficient magnesium intake. It is devoid of any toxicity. Pharmacological magnesium therapy, whatever the magnesium status, causes a iatrogenic magnesium load. It may induce magnesium toxicity. Tocolysis is the one common obstetrical indication for beta mimetics and magnesium. Beta-2 mimetics are the reference tocolytic drugs in most countries. But high doses of beta-2 mimetics for suppression of premature labor are associated to a high incidence of maternal, fetal and neonatal side effects. Tocolysis must then be discontinued or limited to shorter treatments with the lowest possible doses. Nutritional magnesium therapy which palliates gestational magnesium deficiency is efficient and atoxic. Conversely, high doses of intravenous MgSO4 for tocolysis are less efficient and unsafe. Because of its maternal and above all pediatric side effects, this maternal pharmacological magnesium therapy should be abandoned for tocolysis. Investigation of the therapeutic ratio of various magnesium salts before their clinical use could help to determine if other anions different from sulfate could decrease the toxicity. Beta-2 agonists are first line asthma therapy, but their safety is debated. Asthma and Chronic Obstructive Pulmonary Disease (COPD) per se may induce magnesium depletion related to a dysregulation of the control mechanisms of magnesium status. It requires a correction of its causal regulation, but nutritional magnesium supplementation is ineffective. When chronic primary magnesium deficiency coexists with obstructive bronchial disorders, it constitutes a decompensatory factor. Atoxic nutritional magnesium therapy may palliate this coexistent magnesium deficiency. Pharmacological magnesium treatment for obstructive pulmonary diseases is not very efficient with low safety. Combination of palliating nutritional magnesium therapy and of beta-2 mimetics for tocolysis or pulmonary obstructive indications may be beneficial and remain atoxic. Conversely combination of intravenous tocolytic high doses of magnesium and of beta-2 mimetics is contra-indicated because of its dubious efficiency and its possible toxicity. The possible role of SO4- as regards toxicity must be discussed. Contra-indications of lower intravenous or inhaled Mg doses for pulmonary bronchial obstruction are less imperative than for tocolysis. The selection of a particular magnesium salt among others should take into account reliable plasmacological and toxicological data. It seems necessary to determine the therapeutic ratio (LD50/ED50) of the various available magnesium salts before pharmacological use.     

Insulin-like growth factor binding protein concentration and post- translational modification in embryological fluid

Levels of proteolytic activity directed against insulin-like growth factor binding protein 3 (IGFBP-3) and the distribution of phosphorylated isoforms of IGFBP-1 were assessed in matched sample sets of maternal serum, coelomic fluid and amniotic fluid from 21 pregnancies at 6-12 weeks gestation. In addition, concentrations of immunoreactive IGFBP-1 to -3, insulin-like growth factor (IGF)-I and - II were determined in all three compartments in 21 pregnancies, and in coelomic fluid and maternal serum in 58 pregnancies. IGF-I concentrations were highest in maternal serum and similarly low in coelomic and amniotic fluid. IGF-II concentrations were also highest in maternal serum but easily detectable in coelomic fluid where concentrations showed a significant correlation with gestational age. IGFBP-1 concentrations were higher in coelomic fluid than in either maternal serum or amniotic fluid and showed a significant correlation with gestational age in this compartment. Analysis of IGFBP-1 phosphoforms showed clear differences in phosphorylation of IGFBP-1 between groups with maternal serum containing predominantly the phosphorylated forms and coelomic fluid almost exclusively the non- phosphorylated form. First trimester amniotic fluid IGFBP-1 was barely detectable and appeared non-phosphorylated. These findings suggest that the high IGF-II concentrations and lack of inhibitory phosphoforms of IGFBP-1 in coelomic fluid could potentially enhance mitogenic activity in the early human gestational sac. IGFBP-2 concentrations were high in coelomic fluid compared with maternal serum whereas coelomic fluid IGFBP-3 concentrations were intermediate, easily detectable and correlated strongly with gestational age. Protease activity was far less in coelomic fluid than in matched maternal serum samples. Marked differences in both concentrations and post-translational modification of IGFBPs in maternal serum compared with embryonic fluid suggest different regulatory pathways.      

The role of amniotic fluid interleukin-6, and cell adhesion molecules, intercellular adhesion molecule-1 and leukocyte adhesion molecule-1, in intra-amniotic infection

PROBLEM: To determine amniotic fluid concentrations and correlations of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and leukocyte adhesion molecule-1 (LAM-1) in patients with and without intra-amniotic infection. METHOD OF STUDY: Fourteen specimens with intra-amniotic infection and 45 without intra-amniotic infection were studied. Intra-amniotic infection was defined as the presence of a positive amniotic fluid culture. Amniotic fluid IL-6, ICAM-1, and LAM-1 levels were determined by an enzyme-linked immunoassay, and normalized by amniotic fluid creatinine levels. RESULTS: Amniotic fluid concentrations of IL-6 and LAM-1 were significantly higher in patients with than without intra-amniotic infection. However, amniotic fluid ICAM-1 concentrations were not significantly different between two groups. Amniotic fluid IL-6, LAM-1, and ICAM-1 were positively correlated. CONCLUSIONS: Our data indicate that amniotic fluid IL-6 is significantly associated with an increased adhesion molecule expression in intra-amniotic infection. However, LAM-1 plays a more important role than ICAM-1 in intra-amniotic infection.     

Tissue typing amniotic fluid cells: potential use for detection of contaminating maternal cells.

The presence of contaminating maternal cells in amniotic fluid is an important, though infrequent, cause of error in karyotyping the fetus. A method of detecting contaminating maternal cells in amniocentesis specimens by determining the HLA phenotype of the cells of amniotic fluid and the mother is described. Tissue typing of 15 amniocentesis specimens was performed, and in 14 cases the fetal origin of the cells was established. In one case, the results of tissue typing suggested maternal cell contamination, though this had not been suspected from chromosome studies of the amniotic fluid cell cultures. Other possible uses for tissue typing of amniotic fluid specimens for prenatal diagnosis are also described.     

Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener's granulomatosis

Wegener's granulomatosis (WG) is a systemic inflammatory disease with vasculitis as the key feature. Abnormal expression of tumour necrosis factor alpha (TNFalpha) is considered of prime pathogenic importance in several inflammatory diseases. The effects of TNFa are mediated by TNF receptors (TNF-R), and these receptors are often found in soluble forms (sTNF-R), which can modulate TNFalpha actions. To evaluate the clinical importance of the TNF family of cytokines, the serum levels of TNFalpha, TNFbeta, now termed lymphotoxin (LTalpha), and sTNF-R1 and sTNF-R2 were measured by ELISA in 8 patients with WG during active disease and during immunosuppressive treatment, and in 11 healthy controls in parallel. Serum concentrations of TNFalpha were undetectable in all except two controls (18%) and three patients with WG (37%). After 7 days of therapy, six of the WG patients had measurable TNFalpha levels. Examination of the relative amounts of TNFalpha and sTNF-R indicated that TNFalpha was mostly bound to its soluble receptors. In WG, the serum levels of sTNF-R1 and sTNF-R2 were dramatically increased (p<0.01), with little or no variation during treatment. While the IL-1beta levels did not deviate significantly from controls, the IL-1ra levels were significantly elevated in the WG patients throughout the study period (p<0.01).     

Upregulated amniotic fluid cytokines and chemokines in emergency cerclage with protruding membranes

PROBLEM To identify the prognostic factors for pregnancy outcome in women who received emergency cerclage for dilated cervix with protruding membranes. METHOD OF STUDY A prospective cohort study was performed, and a total of 14 women who received emergency cerclage were included. Clinical features and laboratory findings including amniotic fluid cytokines and chemokines were compared between women who had successful pregnancy (survival group, n = 6) and those who had perinatal death (non-survival group, n = 8). Five healthy pregnant women served for normal controls for amniotic fluid study. RESULTS The overall neonatal survival was 42.9% in women with emergency cerclage. Serum C-reactive protein levels on postoperative day 3 and 7 were significantly higher in non-survival group when compared with those in survival group (P = 0.002, P = 0.01). Amniotic fluid levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and monocyte chemoattractant protein-1 levels of the patients were significantly higher than those of normal controls. Amniotic fluid levels of IL-1α, IL-1β, and IL-8 were significantly increased in the non-survival group when compared with those of the survival group. CONCLUSION Systemic and local inflammatory markers including proinflammatory cytokines and chemokines may predict pregnancy outcome in women with emergency cerclage for dilated cervix with protruding membranes.     

类风湿性关节炎患者滑膜液中IL-10、IL-12和sFasL含量的检测

为了研究细胞因子和凋亡分子在类风湿性关节炎(RA)发病中的作用,用ELISA法分析了26例RA患者滑膜液和血清中IL-12、IL-10和可溶性FasL(sFasL)的含量。结果表明RA患者滑膜液中IL-12、IL-10含量分别为(419.9±89.2)pg/ml和(187.7±34.5)pg/ml,外周血中这两种细胞因子的含量均较低,分别为(65.3±34.2)pg/ml(IL-12)和(85.0±12.7)pg/ml(IL-10)。滑膜液中sFasL的含量为266pg/ml,明显高于血清含量(36pg/ml)。这一结果提示,RA患者滑膜液中IL-12含量和sFasL增高,这些炎性细胞因子增高可能参与了关节滑膜中的自身反应性T细胞的活化,继而造成免疫损伤。     

Cervical length and the risk of microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes

The aims of this study were to determine whether sonographically measured cervical length is of value in the identification of microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes (PPROM) and to compare its performance with maternal blood C-reactive protein (CRP), white blood cell count (WBC), and amniotic fluid (AF) WBC. This prospective observational study enrolled 50 singleton pregnancies with PPROM. Transvaginal ultrasound for measurement of cervical length was performed and maternal blood was collected for the determination of CRP and WBC at the time of amniocentesis. AF obtained by amniocentesis was cultured and WBC determined. The prevalence of a positive amniotic fluid culture was 26% (13/50). Patients with positive amniotic fluid cultures had a significantly shorter median cervical length and higher median CRP, WBC, and AF WBC than did those with negative cultures. Multiple logistic regression indicated that only cervical length had a significant relationship with the log odds of a positive AF culture. Transvaginal sonographic measurement of cervical length is valuable in the identification of microbial invasion of amniotic cavity in women with PPROM. Cervical length performs better than AF WBC, maternal blood CRP, and WBC in the identification of a positive amniotic fluid culture.     

Cytokines as mediators for or effectors against rotavirus disease in children

Rotavirus is the most common cause of severe gastroenteritis in young children, but the pathogenesis and immunity of this disease are not completely understood. To examine the host response to acute infection, we collected paired serum specimens from 30 children with rotavirus diarrhea and measured the levels of nine cytokines (interleukin-1beta [IL-1beta], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) using a microsphere-based Luminex Flowmetrix system. Patients with acute rotavirus infection had elevated median levels of seven cytokines in serum, and of these, the levels of three (IL-6, IL-10, and IFN-gamma) were significantly (P < 0.05) higher than those in serum from control children without diarrhea. Patients with fever had significantly (P < 0.05) higher levels of IL-6 in serum than control children, and those with fever and more episodes of diarrhea had significantly (P < 0.05) higher levels of TNF-alpha than those without fever and with fewer episodes of diarrhea. We further demonstrated a negative association (P < 0.05) between the levels of IL-2 and the number of stools on the day on which the first blood sample was collected. Finally, patients with vomiting had significantly (P < 0.05) lower levels of IFN-gamma than those without vomiting. Our pilot study provides evidence that the types and magnitudes of cytokine responses to rotavirus infection in children influence or reflect the clinical outcome of disease. These findings suggest that certain cytokines may play an important role in the pathogenesis of and the protection against rotavirus disease in children and, consequently, may provide directions and insights that could prove critical to the prevention or treatment of this important disease.     

Endogenous Adenosine Down-Modulates Mid-Trimester IntraAmniotic Tumor Necrosis Factor-α Production

Problem  To determine whether adenosine in amniotic fluid down-regulates pro-inflammatory cytokine production.
Method of study  Mid-trimester amniotic fluid from 21 women was incubated ex vivo in the presence or absence of human adenosine deaminase, the enzyme that irreversibly degrades adenosine. After 24 hr, supernatants were assayed by ELISA for tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10. Clinical parameters were obtained after completion of laboratory testing.
Results  Inclusion of adenosine deaminase resulted in a median increase in TNF-α production from 0.9 to 7.3 pg/mL ( P  = 0.0014). IL-6 production exhibited a non-significant median increase from <2.0 to 53.0 pg/mL ( P  = 0.0780). Median IL-10 production increased slightly from a median of <0.2 to 1.3 pg/mL. Adenosine deaminase-stimulated TNF-α production was proportional to parity and unrelated to gestational age, time of delivery, maternal age or indication for amniocentesis.
Conclusion  Adenosine deaminase treatment increases TNF-α production by ex vivo -cultured amniotic fluid. Adenosine contributes to immune modulation in the amniotic cavity.     

High levels of interleukin 10 in serum are associated with fatality in meningococcal disease.

Interleukin 10 (IL-10) suppresses the production of proinflammatory cytokines in vitro and in murine models of endotoxemia and has been suggested as a candidate for treatment of bacterial septicemia. To investigate the role of IL-10 in meningococcal disease, a sandwich IL-10 enzyme-amplified sensitivity immunoassay was used to quantitate IL-10 in serum and cerebrospinal fluid samples from 41 patients with meningococcal bacteremia or meningitis with or without septic shock. High levels of IL-10 were demonstrated in sera from patients with meningococcal septic shock (mean, 21,221 pg/ml; range, 25 to 64,500 pg/ml). All cases involving fatalities had IL-10 levels in serum of > or = 1,000 pg/ml (mean, 23,058 pg/ml; range, 1,000 to 64,500 pg/ml). Patients with meningococcal meningitis without septic shock had comparably low concentrations of IL-10 in serum (mean, 119 pg/ml; range, 0 to 1,050 pg/ml) but exhibited compartmentalized release of IL-10 in cerebrospinal fluid. Concentrations of IL-10 in serum were positively correlated with the previously reported concentrations of tumor necrosis factor alpha, IL-6, and IL-8 in serum in the same patients. We conclude that IL-10 is extensively activated along with the proinflammatory cytokines during the initial phase of meningococcal septic shock and that IL-10 is associated with fatality in meningococcal disease.