sIL-2R Concentrations Research Articles

Chai-Hu-Gui-Zhi-Gan-Jiang-Tang Regulates Plasma Interleukin-6 and Soluble Interleukin-6 Receptor Concentrations and Improves Depressed Mood in Climacteric Women with Insomnia

This study was performed to compare the effects of Chai-hu-gui-zhi-gan-jiang-tang (Saiko-keishi-kankyo-to), an herbal medicine, in improving depressed mood and on plasma interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) concentrations with those of anti-depressants in peri- and post-menopausal women. Ninety patients complaining of menopausal symptoms including insomnia who were diagnosed with mood disorder based on DSM-IV were recruited and separated into two groups (Chai-hu-gui-zhi-gan-jiang-tang group was selected on the basis of SHO for 42 cases, while anti-depressants were used for 48 cases), and plasma IL-6 and sIL-6R concentrations were determined before and after three months of the treatment. There were no significant differences in the decrease in both climacteric and Hamilton depression score after treatment between the two groups. Plasma IL-6 and sIL-6R concentrations were significantly lower in the Chai-hu-gui-zhi-gan-jiang-tang group (-34.8 +/- 15.5% and -22.4 +/- 14.6%, respectively) than in the anti-depressant group (7.5 +/- 4.8% and 2.4 +/- 3.8%, respectively) after 3 months of treatment. Correlations between rate of decrease in climacteric score and plasma IL-6 (R = 0.498, P = 0.0056) and sIL-6R (R = 0.512, P = 0.0045) concentrations were observed. Chai-hu-gui-zhi-gan-jiang-tang reduced plasma IL-6 and sIL-6R concentrations in relation to improvement of depressed mood during treatment. The findings of this study suggest that Chai-hu-gui-zhi-gan-jiang-tang has the potential to decrease morbidity by alleviation of stress reactions in peri- and post-menopausal women.

Serum Proinflammatory Mediators at Different Periods of Therapy inPatients With Multiple Myeloma

Multiple myeloma (MM) is a malignant disease characterized by the clonal proliferation of plasma cells within the bone marrow. Several cytokines have been demonstrated to be involved in the control of growth, progression, and dissemination of MM. We determined serum levels of interleukin-1β (IL-1β), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) in 14 newly diagnosed MM patients. The median age of the patients was 63.4 ± 10.8 years and all of the patients were stage III (classified according to the Durie-Salmon classification). The same parameters were measured in 15 healthy controls. In addition, we also examined the effects of vincristine-adriamycin-dexamethasone (VAD) therapy on the same parameters and mediators as well as the relationship among the parameters in the same patient groups. The serum concentrations of TNF-α, IL-1β, sIL-2R, IL-6, IL-8, and CRP (18.6 ± 3.7 pg/mL, 10.1 ± 2.8 pg/mL, 730 ± 220 U/mL, 11.4 ± 3.3 pg/mL, 23.9 ± 8.3 pg/mL, and 49.9 ± 19.5 mg/dL, resp) were significantly higher in newly diagnosed MM patients than in healthy controls (P < .0001). All of the parameters were found to be significantly reduced after chemotherapy. In conclusion, we found that after the VAD therapy, the level of these cytokines which are thought to play an important role in the pathogenesis of MM was significantly suppressed. This is the first study demonstrating strong impact of VAD treatment on circulating mediators of sIL-2R and IL-8 levels parameters.

Immunomodulatory Activities of Yunzhi and Danshen in Post-treatment Breast Cancer Patients

Breast cancer is the most common cancer among women worldwide. Discomfort and fatigue are usually arisen from anticancer therapy such as surgery, radiotherapy, chemotherapy, hormonal therapy, or combination therapy, because of the suppressed immunological functions. Yunzhi (Coriolus versicolor) can modulate various immunological functions in vitro, in vivo, and in human clinical trials. Danshen (Salvia miltiorrhiza) has been shown to benefit the circulatory system by its vasodilating and anti-dementia activity. The purpose of this clinical trial was to evaluate the immunomodulatory effects of Yunzhi-Danshen capsules in post-treatment breast cancer patients. Eighty-two patients with breast cancer were recruited to take Yunzhi [50 mg/kg body weight, 100% polysaccharopeptide (PSP)] and Danshen (20 mg/kg body weight) capsules every day for a total of 6 months. EDTA blood samples were collected every 2 months for the investigation of immunological functions. Flow cytometry was used to assess the percentages and absolute counts of human lymphocyte subsets in whole blood. Plasma level of soluble interleukin-2 receptor (sIL-2R) was measured by enzyme-linked immunosorbent assay (ELISA). Results showed that the absolute counts of T-helper lymphocytes (CD4+), the ratio of T-helper (CD4+)/T suppressor and cytotoxic lymphocytes (CD8+), and the percentage and the absolute counts of B-lymphocytes were significantly elevated in patients with breast cancer after taking Yunzhi-Danshen capsules, while plasma slL-2R concentration was significantly decreased (all p < 0.05). Therefore, the regular oral consumption of Yunzhi-Danshen capsules could be beneficial for promoting immunological function in post-treatment of breast cancer patients.

Comparison of Pharmacokinetics and Pharmacodynamics of two different dosing regimens of Proleukin® (IL-2) in Combination with rituximab: The effect of NK cell expansion.

Background: Published results from studies testing two different dosing regimens of IL-2 in combination with rituximab have shown that thrice-weekly dosing of IL-2 resulted in greater expression of NK cell as compared to a daily dosing (Gluck, et al. Clin Cancer Res 2004). Expanded NK cells are desired to drive effective rituximab induced ADCC. Here we report on the observed pharmacokinetic (PK) differences associated with the differences in pharmcodynamics (PD) observed with the two regimens.Methods: Two different subcutaneous (SC) IL-2 dosing regimens in combination with rituximab (375 mg/m² weekly IV infusions weeks 1 through 4) were studied: daily IL-2 (6 MIU daily weeks 2–5) versus thrice-weekly IL-2 (14 MIU weeks 2–5) resulting in a total of 42 MIU weekly for each regimen. Serum samples for IL-2, rituximab, and soluble IL-2 receptor (sIL-2r) were analyzed using an ELISA assay. Anti-IL-2 and anti-rituximab antibodies (Ab) were also determined. IL-2 and rituximab serum concentration-time data were analyzed by model-independent methods using WinNolin.Results: Daily dosing of IL-2 exhibited time-dependent pharmacokinetics characterized by lower concentrations of IL-2 upon repeat SC dosing. An increase in IL-2 clearance coincided with an increase in sIL-2r concentrations in the systemic circulation. By the fifth dose, sIL-2r concentrations reached steady state at approximately 2–3 times higher concentrations than the baseline value. In contrast, the thrice-weekly dosing of IL-2 demonstrates no time-dependent kinetics; there were no observed differences in IL-2 plasma concentrations after the first dose or after repeated dosing. Surprisingly, a similar increase in sIL-2r levels from baseline was observed after multiple thrice-weekly dosing of IL-2. The pharmacokinetics of rituximab was similar after daily or thrice-weekly regimens of IL-2 and were comparable to values reported in the literature. The incidences of Ab against IL-2 and rituximab were low (<7%).Conclusion: Concomitant administration of IL-2 with rituximab is well tolerated, with no evidence of pharmacokinetic interaction. Thrice-weekly dosing regimen results in more sustained plasma IL-2 levels with repeated dosing than daily IL-2 dosing. Hence the sustained plasma levels and AUC associated with the thrice-weekly dosing potentially explains why this regimen results in greater NK cell expansion that does the daily dosing.

Acute changes in dietary omega-3 fatty acid intake lowers soluble interleukin-6 receptor in healthy adult normal weight and overweight males

To determine the effect of a short-term isocaloric exchange of alpha-linolenic acid (ALA, 18:3n3) for linoleic acid (LA, 18:2n6) on fasting levels of soluble interleukin-6 receptor (sIL6R), and soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) in healthy normal weight and overweight/obese adult males. Four-day clinical intervention study with 0.5% or 5% of total energy from ALA. Fasting (10 h) blood samples were obtained on the morning of day 5 in both diet treatments to measure sTNFR1, sTNFR2, and sIL6R. Nine normal weight (BMI<25kg/m2) and seven overweight (BMI≥25kg/m2) healthy males. Fasting sIL6R decreased significantly from the control (C) diet following four days on the high ALA isocaloric (ISO) diet in normal weight and overweight/obese subjects (normal weight: C=34.89±3.17ng/ml, ISO=30.91±2.24ng/ml, p<0.05; overweight/obese: C=38.19±3.92ng/ml, ISO=33.57±2.47ng/ml, p<0.05). The dietary intervention did not have a significant effect on fasting sTNFR1 or sTNFR2. The results suggest that an isocaloric exchange of ALA for LA can reduce fasting sIL6R concentration by ∼11% after a four-day dietary intervention in both overweight/obese and normal weight subjects. The data also suggest that longer exposure to a similar diet may have the potential to reduce inflammatory burden and thus lower the risk of both cardiovascular disease as well as diabetes.

Soluble interleukin-6 receptor (sIL-6R) in cerebrospinal fluid of patients with inflammatory and non inflammatory neurological diseases

IL-6 acts on target cells via the ligand-binding protein interleukin-6 receptor (IL-6R) and the affinity-converting and signal-transducing glycoprotein 130 (gp130). Soluble interleukin-6 receptor (sIL-6R) has an agonistic role because the soluble complex (IL-6/sIL-6R) can activate cells that do not express IL-6R and an antagonistic role as it enhances the inhibitory activity of sgp130. Soluble forms of both receptors, sIL-6R and sgp130, regulate the action of IL-6. sIL-6R was measured by a sensitive enzyme-linked immunosorbent assay in paired sera and cerebrospinal fluid (CSF) from 46 patients with inflammatory neurological diseases (IND), 45 patients with relapsing–remitting multiple sclerosis (RR-MS), 13 patients with primary progressive multiple sclerosis (PP-MS), 17 patients with other non inflammatory neurological diseases (NIND) and 13 mentally healthy individuals—healthy controls (HC). Patients with RR-MS had CSF sIL-6R levels comparable to those from patients with IND, but higher than patients with NIND and HC. A positive correlation between the CSF/serum albumin (QAlb) and CSF sIL-6R levels was observed in IND but not in RR-MS patients indicating that CSF sIL-6R levels in IND patients could be influenced by serum sIL-6R and blood brain barrier (BBB) permeability properties. RR-MS patients had higher values of [CSF/serum sIL-6R:CSF/serum albumin] (sIL-6R index) than IND patients suggesting that in multiple sclerosis (MS), the increase in CSF sIL-6R could be due to intrathecal synthesis of sIL-6R. The finding of increased CSF sIL-6R concentrations (>979 pg/ml) with sIL-6R index (>4.66), in correlation with positive oligoclonal bands in RR-MS patients, suggests that values of sIL-6R index > 4.66 indicate intrathecal increase of sIL-6R and might be used as an indicator of neuroimmunoregulatory and inflammatory processes in the central nervous system (CNS).

Acute changes in dietary omega-3 fatty acid intake lowers soluble interleukin-6 receptor in healthy adult normal weight and overweight males

Objective To determine the effect of a short-term isocaloric exchange of alpha-linolenic acid (ALA, 18:3n3) for linoleic acid (LA, 18:2n6) on fasting levels of soluble interleukin-6 receptor (sIL6R), and soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) in healthy normal weight and overweight/obese adult males. Design Four-day clinical intervention study with 0.5% or 5% of total energy from ALA. Fasting (10 h) blood samples were obtained on the morning of day 5 in both diet treatments to measure sTNFR1, sTNFR2, and sIL6R. Subjects Nine normal weight ( BMI<25 kg/ m 2 ) and seven overweight ( BMI≥25 kg/ m 2 ) healthy males. Results Fasting sIL6R decreased significantly from the control (C) diet following four days on the high ALA isocaloric (ISO) diet in normal weight and overweight/obese subjects (normal weight: C=34.89±3.17 ng/ ml , ISO=30.91±2.24 ng/ ml , p<0.05; overweight/obese: C=38.19±3.92 ng/ ml , ISO=33.57±2.47 ng/ ml , p<0.05). The dietary intervention did not have a significant effect on fasting sTNFR1 or sTNFR2. Conclusions The results suggest that an isocaloric exchange of ALA for LA can reduce fasting sIL6R concentration by ∼11% after a four-day dietary intervention in both overweight/obese and normal weight subjects. The data also suggest that longer exposure to a similar diet may have the potential to reduce inflammatory burden and thus lower the risk of both cardiovascular disease as well as diabetes.

This month in Gastroenterology

Interleukin-6 (IL-6) has a central role in regulating the immune response and inflammation. One of its mechanisms of action is mediated by forming a complex with soluble IL-6 receptor (sIL-6R), allowing it to activate cells lacking IL-6 receptors (IL-6R). In active Crohn’s disease (CD), serum concentrations of sIL-6R are increased and serum IL-6 and sIL-6R concentrations correlate with C-reactive protein (CRP) levels. Furthermore, the levels of IL-6 and sIL-6R in colonic organ cultures are elevated in patients with CD, especially in those with active inflammation. Several preclinical studies have also shown that blocking antibodies to IL-6 can reduce inflammation, disease severity, and cause lymphocyte apoptosis. These observations provided the basis for this pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA in patients with active Crohn’s disease. MRA (Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) is a humanized anti-human IL-6R monoclonal antibody (mAb) that binds to both membrane-bound form and soluble form of human IL-6R with high affinity and specificity. It was constructed by grafting the complementarity-determining regions of the mouse anti-human IL-6R mAb into human IgG1 to re-create a properly functioning antigen-binding site in a reshaped human antibody. Patients with active Crohn’s disease were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. A reduction of the Crohn’s Disease Activity Index (CDAI) by 70 points was used as the study’s primary endpoint. The study by Ito et al. found that 80% of the patients given biweekly MRA had a significantly better clinical response rate as compared with 31% of the placebo-treated patients (Figure 1). Twenty percent of the patients (2 of 10) on this regimen went into remission as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every 4-week regimen was 42% (5 of 12). No differences in endoscopic and histological examination were noted between MRA and placebo groups. The incidence of adverse events was similar in all the groups. Although preliminary, these data show that biweekly 8 mg/kg infusion of MRA is well tolerated, normalizes the acute-phase responses, and appears to be clinically effective in active Crohn’s disease. More studies are needed to corroborate these preliminary results and to determine optimal dosing and toxicity issues.

Clinical significance of the soluble interleukin-2 receptor as a putative systemic nutritional index in the elderly*

Background: The clinical significance of a slight increase in serum soluble interleukin-2 receptor (sIL2R) concentration in the stable elderly was investigated. Methods: The subjects consisted of 35 residents of nursing homes with physical impairment as a sequela to cerebral infarctions, who had no inflammatory conditions, and were not receiving anodyne or immunological treatment. They were divided into two groups: 24 subjects without overt or suspected malignancy (NC) and 11 with a history of malignancy (CA). Serological screening with measurement of sIL2R concentrations was performed and numbers of lymphocytes with CD4 and CD8 markers were determined. The NC group was subdivided into control subjects (n = 15, sIL2R < = 883 U/mL) and subjects demonstrating elevated concentrations of sIL2R (n = 9, NH), as in a previous study. Results: Between the NH and control groups, differences were found in serum concentrations of albumin, blood urea nitrogen, total cholesterol concentration, Pettigrew's prognostic nutritional index (PNI) and activities of daily living score, but not in age or sex. Factor analysis in the NC group showed serum creatinine and blood urea nitrogen concentrations to be correlated positively, and serum albumin, total cholesterol concentrations, activities of daily living score, and PNI to be correlated negatively with sIL2R. Differences were found in sIL2R, albumin, total protein, total cholesterol, β-lipoprotein and PNI between the CA and control groups, but no correlations among these parameters were found in the CA group. There was no difference in the rate of positive test results for rheumatoid factor between the NC and CA, or control and NH groups. The survival rate of control subjects over 24 months was better than that of NH subjects, but not that of CA subjects. Conclusion: Our results suggest that a slight increase in the concentration of sIL2R is related to subclinical systemic deterioration, especially regarding nutrition, with a plausible connection to prognosis, in stable elderly patients without malignancy.

Serum sIL-2R, TNF-α and IFN-γ in alveolar echinococcosis

to approach the relationship between alveolar echinococcosis (AE) pathology and level of sIL-2R,TNF-alpha and IFN-gamma in sera and the significance of cytokines in development of AE. After 23 patients with AE were confirmed by ELISA and ultrasound, their sera were collected and the concentrations of sIL-2R,TNF-alpha and IFN-gamma were detected by double antibody sandwich. Twelve healthy adults served as controls. According to the status of livers of AE patients by ultrasound scanning, they were divided into 4 groups: P(2), P(3), P(4) groups and C group (control). Average of concentrations of sIL-2R,TNF-alpha and IFN-gamma in homologous group was statistically analyzed by both ANOV and Newman-Keuls, respectively. The mean of sIL-2R in P(2) group was 97+/-29, P(3): 226+/-80, P(4): 194+/-23 and control group (111+/-30)X10(3) u/L (P<0.01). The mean of TNF-alpha in P(2) group was 1.12+/-0.20, P(3): 3.67+/-1.96, P(4): 1.30+/-0.25 and control group 0.40+/-0.19 mug/L (P<0.01). The mean of IFN-gamma in P(2) group was 360+/-20, P(3): 486+/-15, P(4): 259+/-19 and control group: 16+/-2 ng/L (P<0.01). Judged by ANOV and Newman-Keuls, the mean concentrations of sIL-2R, TNF-alpha and IFN-gamma had a significant difference among groups. Except for P(2) group, the mean sIL-2R between other groups of AE patients had a significant difference (P<0.05). The mean of TNF-alpha concentration in P(3) group was the highest (P<0.01). The mean of IFN-gamma concentration in all patients was higher than that in control group (P<0.01), but there was no difference between AE groups (P>0.05). Low sIL-2R level indicates an early stage of AE or stable status, per contra, a progression stage. Higher level of TNF-alpha might be related to the lesion of liver. The role of single IFN-gamma is limited in immunological defense against AE and it can not fully block pathological progression.

Altered expression of inflammatory cytokines in primary osteoarthritis by human T lymphotropic virus type I retrovirus infection: a cross-sectional study

Human T cell leukaemia virus type I (HTLV-I) is known to be involved in late-onset chronic polyarthritis as HTLV-I-associated arthropathy. However, it is unclear whether HTLV-I infection could modify the pathophysiology of osteoarthritis (OA). In this study we compared several inflammatory cytokines, such as C-terminal parathyroid hormone-related peptide (C-PTHrP), soluble interleukin-2 receptor (sIL-2R) and interleukin (IL)-6, and an osteo-destruction marker, deoxypyridinoline, in synovial fluid (SF) samples obtained from 22 HTLV-I carriers and 58 control non-carrier patients with OA. These patients were diagnosed clinically and radiographically with primary OA affecting one or both knee joints, and were similar with regard to age, sex and clinical symptoms. We also performed histopathological examination as well as immunohistochemistry of HTLV-I-derived Tax protein in eight synovial tissues taken from carrier patients. C-PTHrP in SF was significantly higher in HTLV-I carriers (287 ± 280 pM) than in non-carriers (69 ± 34 pM), and the concentration in 13 carriers was above the upper range of OA. In HTLV-I carriers, the concentrations of sIL-2R (741 ± 530 IU/ml), IL-6 (55 ± 86 ng/ml) and deoxypyridinoline (3.1 ± 1.8 nM) were higher than in non-carriers (299 ± 303, 2.5 ± 4.0, 0.96 ± 1.0, respectively), and correlated positively with C-PTHrP. C-PTHrP, sIL-2R and IL-6 concentrations in SF positive for IgM antibody against HTLV-I antigen, a marker of persistent viral replication, were higher than of IgM-negative SF. Histologically, five and two synovia showed mild and moderate synovial proliferation with or without some degree of inflammatory reaction, respectively, and could not be distinguished from OA. Tax-positive synoviocytes were observed sparsely in all samples, and often appeared frequently in actively proliferating regions. Our results suggest that although HTLV-I infection does not necessarily worsen the clinical outcome and local synovitis, the virus can potentially modify the pathophysiology of OA by increasing the inflammatory activity in a subset of carrier patients, especially those with IgM antibody. Longitudinal studies are required to assess the association between HTLV-I infection and OA.

Receptores solubles de la interleucina 2 y del factor de necrosis tumoral en la cirrosis hepática de diversas etiologías. Relación con el pronóstico y la gravedad clínica

The mechanism responsible for the beginning and progression of hepatic injury in liver cirrhosis of viral and alcoholic etiology are unknown currently. However, there are abnormalities in the immune system which may be implied in the pathogenesis. The concentrations of the soluble receptor of tumor necrosis factor (sTNF-R55) and the soluble receptor of interleukin-2 (sIL-2R) in 49 cirrhotic patients were determined by enzyme-linked inmunoassay. Patients were grouped according to the etiology (33 alcoholic and 16 viral) and prognosis (Child-Pugh classification) and they were compared with the values obtained in 26 healthy non-drinkers who made up the control group. The concentrations of sTNF-R55 and sIL-2R were significantly higher in both groups of patients when compared with controls. We found significant differences in sTNF-R55 concentrations in viral and alcoholic but not in sIL-2R concentrations. There was a positive correlation between the concentrations of both receptors and the degrees of Child-Pugh classification, as well as with albumin, total bilirubin and alkaline phosphatase (all of them parameters related to the severity and prognosis of liver cirrhosis). The serum concentrations of soluble receptors of tumor necrosis factor and interleukin-2 correlate with the prognosis of liver cirrhosis independently of its etiology. This fact may reflect the stimulation of T lymphocytes, monocytes and macrophages, in liver cirrhosis.

Cyclosporine A effectively inhibits graft-versus-host disease during development of Epstein-Barr virus-infected human B cell lymphoma in SCID mouse.

We previously constructed human peripheral blood lymphocyte (hu-PBL)/severe combined immunodeficiency mouse (SCID) chimeras and induced human B-cell lymphomas associated with Epstein-Barr virus (EBV) in SCID mice. However, a number of SCID mice died of graft-versus-host disease (GVHD) during the early experimental course. The aim of this study was to test the efficacy of cyclosporine A (CSA) for prevention of GVHD and to define how CSA inhibits the occurrence of GVHD and the production of soluble interleukin (IL) 2 receptor (sIL-2R) in hu-PBL/SCID mice. No mouse died in the active EBV infection group with CSA administration, while 17 mice in three groups without CSA administration died of GVHD. Mortalities in these three groups were 55.56% (5/9), 30.43% (7/23), and 27.78% (5/18), and the medium life span was 17 days. Over the first 33 days after hu-PBL transplantation, serum level of human sIL-2R in hu-PBL/SCID chimeras was stable in the active EBV infection plus CSA group, while sIL-2R concentration gradually increased in the sera of mice with active EBV infection without CSA administration and peaked at 22 days. Thirty-two mice developed tumors among the 43 surviving SCID mice. There was no significant difference of tumor incidence between the active EBV infection groups with CSA and without CSA administration (P > 0.05). From their morphological and immunohistochemical features, as well as detection of human Alu-sequence and EBV in tumor cells, these EBV-induced tumors were identified as human B-cell lymphomas. Thus, CSA can strikingly inhibit GVHD in hu-PBL/SCID chimeras, and should therefore be effective to establish a stable SCID mouse model of human lymphoma associated with EBV. Treatment with CSA had no effect on the tumor incidence in hu-PBL/SCID chimeras after active EBV infection. Accordingly, serum level of sIL-2R is a valuable indicator of GVHD occurrence in hu-PBL/SCID chimeras.

IL-16 in the airways of lung allograft recipients with acute rejection or obliterative bronchiolitis.

Acute rejection (AR) is the principal risk factor for obliterative bronchiolitis (OB), the major complication of lung transplantation. It is known that activated CD4+ T lymphocytes are involved in the development of AR and that interleukin (IL)-16 can inhibit the activity of CD4+ T lymphocytes. In this study, we evaluated whether the concentration of IL-16 in the airways is altered in AR or OB and, if so, how this IL-16 concentration relates to the number or activity of airway lymphocytes. The concentration of IL-16 protein was measured in bronchoalveolar lavage (BAL) fluid at three time-points in lung allograft recipients with either AR or OB and in matched controls using ELISA. The concentration of soluble IL-2 receptor (R) protein was measured in BAL fluid using ELISA as well, as an indicator of lymphocyte activity. The percentage of airway lymphocytes was evaluated by performing BAL differential cell counts. Lung allograft recipients with AR displayed lower IL-16 concentrations compared with matched control patients and this IL-16 concentration correlated negatively with the sIL-2R concentration, but it did not correlate with the percentage of lymphocytes in BAL fluid. In contrast, in BAL fluid from lung allograft recipients with OB, the IL-16 concentration was not altered compared with matched control patients and it did not correlate with the percentage of lymphocytes or with the sIL-2R concentration. These data are compatible with an increase in IL-16 playing a protective role against AR but not against OB and, hypothetically, this type of protective effect could be exerted via a down-regulation of the activity of T lymphocytes.

Changes of interleukin 6 and soluble IL-6 receptor levels after surgery

To investigate alterations in postoperative levels of IL-6 and soluble IL-6 receptor (sIL-6R), we examined their levels in serum and drainage fluids from patients who underwent thoracoabdominal surgery. Serum IL-6 levels reached maximum within the first postoperative day and decreased thereafter. The IL-6 levels were significantly correlated with surgical trauma as defined by the operation time and volume of blood loss during operation. The IL-6 levels in the drainage fluid were much higher than in the serum (458±101-fold; mean±S.E.M.) in the early postoperative phase. IL-6 mRNA was detected in leukocytes from the drainage fluid, but not from the peripheral blood. A large quantity of sIL-6R levels was present in blood samples. The time course of serum sIL-6R levels showed no significant change. sIL-6R concentrations in the drainage fluid were significantly lower than in serum (4.5±1.1-fold; mean±S.E.M.) in the early postoperative phase. We propose that IL-6 is produced in the operative field and enters the peripheral blood stream to induce elevation of serum IL-6. Its levels are influenced by surgical trauma. sIL-6R is being constantly produced in areas other than the operative field, while sIL-6R level is reduced by consumption in the operative field. sIL-6R supplement mechanisms to cope with surgical stress, together with its ligand IL-6, may thus exist.

Mediators of Inflammation in Children with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) in children remains a challenging problem. Crohn disease and ulcerative colitis are characterized by an activation of intestinal mononuclear cells and T-cells within the inflammed lesions. In the present study, we determined whether circulating inflammatory mediators, such as interleukins and adhesion molecules, may represent useful markers of immune activation in vivo. Serum concentrations of IL-2, IL-6, IL-8, IL-10, sIL-2R, sICAM-1 and sVCAM-1 were measured by a quantitative enzyme-linked immunosorbent assay (ELISA) in 18 patients with IBD and 25 healthy subjects matched for age and sex (control group). According to our results, all the inflammatory mediators are significantly increased in patients with IBD as compared to the control group. Pro-inflammatory mediators (IL-6, IL-8, IL-10) are elevated in the serum of patients with active disease, suggesting that they act as naturally occuring initiators of the acute inflammatory process. Increased IL-2 and sIL-2R levels reflect T-cell activation. Increased circulating sICAM-1 and sVCAM-1 levels may reflect increased adhesiveness and signal transmission across cells, probably as a result of shedding of the parent molecule during local cellular immunoresponses in vivo. The measurement of inflammatory mediators may be a useful adjunct to the clinical assessment and to the routine laboratory testing of IBD pediatric patients.

Acute effect of hemodialysis on serum levels of the proinflammatory cytokines.

Chronic inflammation is a common feature of end-stage renal disease, which carries a heightened risk of atherosclerosis and other co-morbid conditions. Dialysis treatment per se can bring additional risk factors for inflammation, such as increased risk of local graft and fistula infections, impure dialysate or bio-incompatible membranes. Our study was designed to determine whether a hemodialysis session leads to an acute substantial alteration in the plasma levels of the proinflammatory cytokines interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha, the T-lymphocyte activation factor soluble IL-2 receptor (sIL-2R), and an inflammation mediator and chemotactic granulocyte factor, IL-8, in end-stage renal disease patients receiving chronic intermittent HD. In this study, 21 (12 male/nine female) patients undergoing chronic hemodialysis were enrolled. The acute effect of a hemodialysis session on serum cytokine concentrations was assessed by comparison of pre-hemodialysis and post-hemodialysis determinations. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha levels were determined with chemiluminescence enzyme immunometric assays. A significant difference was not observed for IL-1beta, IL-6, TNF-alpha, and sIL-2R concentrations in pre-hemodialysis and post-hemodialysis specimens (p>0.05). Serum median (25th-75th percentiles) IL-8 concentration was 69.4 (34.9-110.3) pg/ml before hemodialysis, and decreased to 31.5 (18.0-78.8) pg/ml following hemodialysis (p: 0.006). Clearance of IL-8 increased by 0.47+/-0.08 pg/ml for each unit increase in pre-dialysis IL-8 (p<0.001) and decreased by 5.63+/-2.59 pg/ml for each unit increase in pre-dialysis urea mmol/l (p<0.05). In conclusion, the results of our study demonstrate that a hemodialysis session markedly decreases IL-8 concentration, which is significantly affected by pre-dialysis concentrations, indicating that removal of IL-8 is a concentration gradient-dependent action, but does not change the serum levels of IL-1beta, sIL-2R, IL-6, and TNF-alpha, underlining importance of the structural characteristics of the molecules.

Increased soluble interleukin-6 receptor in vitreous fluid of proliferative vitreoretinopathy

Purpose. To clarify the effect of the interaction between interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on retinal pigment epithelial (RPE) cell proliferation in proliferative vitreoretinopathy (PVR). Methods. Concentrations of IL-6 and sIL-6R molecules in vitreous fluids were measured in eyes with PVR and idiopathic macular hole (MH), and the localization of IL-6 and IL-6R on the PVR fibrous membrane was studied. Production of IL-6 and sIL-6R by cultured RPE cells and the effect of the IL-6/sIL-6R complex on growth of cultured RPE cells were analyzed. Results. Positive staining of IL-6 and IL-6R was observed in proliferating membranes in all PVR cases. IL-6 and sIL-6R concentrations in vitreous fluid from eyes with PVR were significantly higher than in eyes with MH (p < 0.05). A timedependent increase in IL-6 molecules was identified in the culture medium of RPE cells, although sIL-6R was not detected. Dose-dependent growth of RPE cells was observed in the three concentrations (50, 100, and 500 ng/ml) of sIL- 6R used. Conclusions. IL-6 derived from blood during the breakdown of the blood-retinal barrier (BRB) and produced by RPE cells and hematogenous sIL-6R cause RPE proliferation.

Correlation of serum tumor necrosis factor-alpha, interleukin-4 and soluble interleukin-2 receptor levels with radiologic and clinical manifestations in active pulmonary tuberculosis.

The precise clinical manifestations of tuberculosis are likely to result from a complex interaction between the host and the pathogen. We took serum samples from a group of patients with a variety of clinical and radiological stages of pulmonary tuberculosis in order to characterize tumor necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and soluble interleukin-2 receptor (sIL-2R) response. We further evaluated whether the levels of TNF-alpha, IL-4 and soluble IL-2R are related with each other, and also evaluated the levels of TNF-alpha, IL-4 and sIL-2R after anti-tuberculosis therapy and relation with radiologic scores. Forty-three inpatients with active pulmonary tuberculosis and 19 healthy controls participated in the study. Patients were divided into four categories radiologically on chest X-ray (minimal, moderate-advanced, far-advanced and with miliary infiltration). Concentrations of TNF-alpha (20.9+/-10/15.4+/-8 pg/ml) and sIL-2R (2569+/-842/1444+/-514 pg/ml) were statistically different between patients and controls (p=0.02 and p=0.0001, respectively). Before chemotherapy there was a positive correlation between TNF-alpha and sIL-2R (r=0.34), but there was no correlation between IL-4 and TNF-alpha, and between IL-4 and sIL-2R (r=-0.23 and r=-0.22). The TNF-alpha level was not statistically different in four groups before and after chemotherapy. Results of this study provided some evidence confirming the previously reported role of TNF-alpha, IL-4 and sIL 2R in the control of tuberculosis, but these cytokines were not found related with disease severity.

Nonspecific plasma proteins during sublingual immunotherapy.

Usually, specific allergy-related plasma proteins such as immunoglobulin E (IgE) and immunoglobulin G (IgG) are used for estimating the grade of sensitization and follow-up of immunotherapy. In recent years, several nonspecific inflammatory markers, such as sICAM-1 and sIL-2R, have been shown as being suitable for therapy control in allergy. In our investigation of patients under sublingual immunotherapy (SLIT), plasma from 42 healthy controls and 133 children with single inhalation allergies to grass pollen, birch pollen or house dust mites was obtained during the symptom-free period. Patients showed symptoms including allergic rhinitis, dermatitis and allergic asthma with one single RAST class 3 or higher. Plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble interleukin-2 receptor (sIL-2R), sE-selectin, interleukin-12 (IL-12) and specific IgG4 were analyzed with the ELISA technique. After 1 year of SLIT, concentrations of sICAM-1, sIL-2R and sE-selectin declined significantly when results from all patients were taken as one group. Regarding the single allergen groups, the sICAM-1 and sIL-2R decrease was significant in the grass and mite group, but not in the birch group, while the sE-selectin decline was only significant in the birch group after 1 year of SLIT, but not in the grass and the mite group. No difference was observed in IL-12 and IgG4 expression. In two groups of controls with a mean age of 9.5 versus 17.5 years, the analyzed parameters were not age-dependent. The increased proteins may be useful as additional markers for the evaluation of immunological effects and follow-up investigations of allergy therapies.