Induction of interleukin-6 during human immunodeficiency virus infection

Interleukin-6 (IL-6), a multifunctional cytokine produced in monocytes, fibroblasts, and other cell types, is induced by a variety of stimuli, including bacteria, viruses, and other cytokines. When normal monocyte cultures were exposed to a monocytotropic strain of human immunodeficiency virus (HIV), HTLV-IIIBa-L, significant levels of IL-6 bioactivity were detected in the culture supernatants after 12 to 43 days of incubation, at a time when there was associated evidence of HIV production. Similarly, when normal monocyte cultures were cocultured with peripheral blood mononuclear cells from HIV-infected individuals, HIV replication in these cultures was associated with production of IL-6. In further studies, we determined that mean serum levels of IL-6 bioactivity were abnormally elevated in HIV-seropositive individuals with stage 1/2 infection (25.2 x/divided by 1.8 U/mL) and stage 3/4 infection (46.1 x/divided by 1.7 U/mL) when compared with normals (1.6 x/divided by 1.2 U/mL). In contrast mean serum IL-6 levels were not different from normal in stage 5/6 infection (2.7 x/divided by 1.6 U/mL). A selected group of 12 HIV-seropositive individuals (stages 1, 2, and 3) who harbored HIV capable of replicating in T cells but not in monocyte cultures had a mean serum IL-6 level of 5.3 U/mL (x/divided by 1.5), a value significantly lower (P less than .004) than that measured in control HIV-seropositive individuals infected with monocytropic HIV (39 x/divided by 1.9 U/mL). In addition, serum IL-6 levels in HIV-seropositive individuals (stages 1 through 6) correlated directly with serum immunoglobulin G (IgG) levels (R = .74, P less than .001). Monocytes but not T cells are capable of a high level IL-6 production in vitro, and monocyte-derived IL-6 stimulates Ig production in activated B cells. Thus, HIV-seropositive individuals who often are infected with monocytotropic HIV and often display abnormally elevated serum IgG levels may exhibit these abnormalities as a consequence of abnormally elevated IL-6 levels induced by HIV.     

In vivo cytokine and neuroendocrine responses to endotoxin in human immunodeficiency virus-infected subjects.

The cytokine and neuroendocrine host responses to experimental challenge with lipopolysaccharide (LPS) were studied in human immunodeficiency virus (HIV)-infected subjects and uninfected control subjects. Elevations in circulating concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were significantly greater in HIV-infected subjects than control subjects after LPS challenge. All subjects showed a significant increase in circulating concentrations of adrenocorticotropin, cortisol, and norepinephrine after LPS challenge, but there was not a significant difference between the responses of these hormones in the HIV-infected and -uninfected subjects. Compared with the control subjects, the HIV-infected subjects had a significantly reduced IL-10 response and a reduced IL-1 receptor antagonist response. It is concluded that the TNF-alpha, IL-6, IL-8, and IL-10 cytokine responses to LPS in vivo are disrupted in HIV subjects but that this is not related to disruption of the hypothalamo-pituitary-adrenal axis.     

Immunoglobulin G3-specific antibodies as a marker for early diagnosis of HIV infection in children.

Early diagnosis of HIV infection in the child of an HIV-infected mother may be difficult as HIV-specific immunoglobulin (Ig) G antibodies are transmitted to the fetus transplacentally. In an attempt to provide a new, simpler tool for early identification of HIV-infected children we analysed the HIV-specific IgG subclass pattern during the first year of life. One hundred and one samples were collected from 35 children born to HIV-seropositive mothers, among whom 18 seroreverted during follow-up and 17 were HIV-infected (two P1 and 15 P2 according to the Centers for Disease Control classification). Serum HIV-specific IgG3 was detectable at least in one sample in 26 out of 35 children. All 17 HIV-infected children showed persistently detectable specific IgG3, both with stable or progressive disease. Out of the 18 uninfected children who seroreverted during follow-up, nine were HIV-specific IgG3-negative when first tested and nine lost HIV-specific-IgG3 within 28 weeks after birth. The correlation of the serological results with clinical information and any other diagnostic tool on each child suggests that the clearance of specific-IgG3 antibodies heralds seroconversion in uninfected passive antibody-carrier children. This observation provides the basis for a new, simple and effective method for early diagnosis of HIV infection in children born to seropositive mothers.     

Correlation of virus load and soluble L-selectin, a marker of immune activation, in pediatric HIV-1 infection

OBJECTIVE: HIV infections in children are characterized by high viral load and, in some perinatally infected newborns, delayed appearance of viral markers. Both phenomena may be related to different levels of immune activation affecting viral replication. This study was designed to investigate the relationship between immune activation and viral replication in pediatric HIV infection, and the role of pre-existent immune activation in facilitating HIV transmission to the fetus/newborn. DESIGN: Plasma levels of soluble L-selectin (s-LS), an immune activation marker, were determined in 100 infants with perinatally transmitted HIV infection, compared with 106 age-matched HIV-exposed uninfected controls. Included in the analysis were samples from 31 HIV-infected (10 PCR+ and 21 PCR-) and 35 uninfected newborns aged < 2 days. METHODS: To determine s-LS levels, a solid phase ELISA was performed on plasma samples of patients and controls. Results: s-LS levels in uninfected children were higher than those in normal adults. HIV-infected patients had more rapidly increasing values in the first 6 months of life compared with uninfected infants. Plasma s-LS levels correlated with HIV viral loads (r, 0.50). Among newborns in the first 2 days of life, s-LS levels were lowest in those with negative PCR tests, compared with PCR-positive or uninfected infants. CONCLUSIONS: These results suggest that higher immune activation in children contributes to higher viral loads, and that the level of pre-existent immune activation may have a role in determining which infants have detectable virus in peripheral blood at birth.     

Energy balance, viral burden, insulin-like growth factor-1, interleukin-6 and growth impairment in children infected with human immunodeficiency virus

OBJECTIVE: To determine the relationship between energy metabolism and growth abnormalities in HIV-infected children and to assess clinical or laboratory characteristics which may be contributing factors to their growth impairment. DESIGN: A comparative study. METHODS: We measured energy intake by inpatient calorie count/outpatient 24 h food recalls, resting energy expenditure by indirect calorimetry, total energy expenditure by the doubly-labeled water technique, iron metabolism, protein metabolism, and lipid metabolism markers as well as CD4 count, viral load, insulin-like growth factor-1 (IGF-1), serum interleukin-6 (IL-6), and whole blood stimulated IL-6 levels in prepubertal congenitally HIV-infected children with normal and impaired growth patterns. RESULTS AND CONCLUSIONS: Differences in energy expenditures were not found between normal and growth-impaired HIV-infected children. Energy intake but not energy expenditure was significantly reduced when HIV-infected children were compared to expected normal values for age and gender. Advanced HIV clinical disease, severe immune suppression, increased viral burden, increased IL-6 activity, decreased total serum protein, and decreased IGF-1 levels were more likely to be found in HIV-infected children with growth impairment in comparison with HIV-infected children with normal growth.     

Antibody-dependent cell-mediated cytotoxicity against cells infected with the human immunodeficiency virus

Human immunodeficiency virus (HIV) elicits the production of virus-specific antibodies in infected individuals. We investigated the ability of serum from HIV-infected individuals to mediate antibody-dependent cellular cytotoxicity in an in vitro 51Cr release assay system. Fresh peripheral blood mononuclear cells from healthy donors seronegative for HIV were used as cellular effectors against HIV-infected and uninfected H9 target cells in the presence of serum from HIV-infected or uninfected donors. Serum from HIV-infected, but not uninfected, donors significantly augmented cytolysis of virus-infected targets (P less than .005). There was no augmented killing of uninfected H9 cells with sera from either group. Studies using serum from mice that had been immunized with synthetic peptides from the HIV envelope region suggested that this response is directed, at least in part, at several determinants of the transmembrane portion of the HIV envelope glycoprotein.     

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathy

This study determined the concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1) and soluble E-selectin (sE-selectin) in cerebrospinal fluid (CSF) and serum from 15 children with influenza virus-associated encephalopathy to determine the role of cytokines in the pathogenesis. Cytokines and sTNFR1 were measured by enzyme-linked immunosorbent assay. The CSF IL-6, TNF-alpha and sTNFR1 concentrations were elevated in 9, 4 and 4 of 12 children, respectively. The serum concentrations of IL-6, TNF-alpha, sTNFR1 and sE-selectin were elevated in 10, 2, 5 and 7 of 13 children, respectively. Four children with elevated TNF-alpha and sTNFR1 levels in the CSF had neurological sequelae. The results suggested that cytokines not only in serum but also in CSF play a pivotal role in influenza virus-associated encephalopathy, and that the CSF TNF-alpha and sTNFR1 levels may be important for predicting neurological sequelae.     

Serum concentrations of antiphospholipid and anticardiolipin antibodies are higher in HIV-infected women

Manifestations of viral infections like human immune deficiency virus (HIV) differ between women and men. There are some reports due to a higher risk of thrombosis due to antiphospholipid syndrome in HIV-infected women compared with men. The purpose of this study was demonstrating the impact of gender on serum concentration of antiphospholipid and anticardiolipin antibodies in HIV-infected patients. A total of 58 HIV-infected patients and 58 age, sex-matched healthy adults were enrolled. We measured platelets count, hemoglobin, partial thromboplastin time (PTT); prothrombin time (PT), international normalized ratio (INR), antiphospholipid IgG/IgM and anticardiolipin IgG/IgM serotypes in our studied population. Age, male-to-female ratio, hemoglobin level, PT, INR, antiphospholipid IgM isotype, anticardiolipin IgM and IgG isotypes levels were not significantly different between HIV-infected patients and healthy individuals, when CD4+ T-cell count, CD8+ T-cell count, platelet count, and PTT were significantly lower, and antiphospholipid IgG isotype levels was significantly higher in HIV patients. Antiphospholipid IgG isotypes (3.2 [2.8–4.2] vs. 2.5 [2.3–3.1]; P?<?0.001) and anticardiolipin IgG isotypes (2.2 [1.9–2.7] vs. 1.4 [1.4–1.9]; P?<?0.001) were significantly higher in HIV-infected women than in HIV-infected men. Antiphospholipid IgG/IgM and anticardiolipin IgG/IgM were significantly correlated in HIV-infected men and women when they did not had any correlation in controls. We suggest that HIV infection accelerate thrombosis in women more profoundly than in men, as a result of differences in disease progression and response to therapy in these patients.     

Possible Role of Interleukin-10 (IL-10) and CD40 Ligand Expression in the Pathogenesis of Hypergammaglobulinemia in Human Immunodeficiency Virus Infection: Modulation of IL-10 and Ig Production After Intravenous Ig Infusion

The mechanisms leading to polyclonal hypergammaglobulinemia inpatients with human immunodeficiency virus (HIV) infection are not wellunderstood. In light of the important role of interleukin-10 (IL-10)and the interaction between CD40 and CD40 ligand in the normalregulation of B-lymphocyte function and Ig production, we examinedthese parameters in 24 HIV-infected patients. Both plasma IL-10 levelsand the percentage of CD4⁺ and CD8⁺lymphocytes expressing CD40 ligand were significantly higher in thepatients than in the 10 blood donor controls. Serum IgG correlatedpositively with circulating IL-10 levels and the percentage ofCD4⁺ lymphocytes expressing CD40 ligand. Furthermore, asingle bolus infusion of intravenous Ig (0.4 g/kg) in 8 HIV-infectedpatients caused a further increase in IL-10 levels in plasma and anincrease in both IL-10 and IgG production in peripheral bloodmononuclear cell cultures. In another patient group (Wegener'sgranulomatosis) receiving a single bolus infusion of intravenous Ig, asimilar increase in plasma IL-10 levels was found, suggesting that this may be a general effect of intravenous Ig. In patients with HIV infection, our data suggest that a vicious cycle may be operative wherehigh endogenous Ig levels may enhance IL-10 production that, in turn,leads to higher Ig production.     

Diagnosis of perinatally acquired HIV-1 infection using an IgA ELISA test

The clinical utility of the detection of anti-HIV-1 IgA antibodies using a modified commercial ELISA (EIA) test for the early diagnosis of perinatally acquired HIV-1 infection was evaluated. One hundred and seventeen sera were obtained from 86 infants born to HIV-1-infected mothers and tested for HIV IgA antibodies by an ELISA test (third generation) after removal of IgG with recombinant protein G. Infants were classified according to the Center for Disease Control and Prevention's (CDC) classification system after 15 months of age; 46 were classified as HIV-infected children and 40 as uninfected. HIV-IgA antibodies were detected in 53 of 64 serum samples from all infected children. No significant differences were observed in IgA detection among symptomatic or asymptomatic infected children. However, when analyzed by age a significant difference was observed in IgA detection when children who were over 6 months of age were compared with the younger group (Fisher exact test, p = 0.0000053). All 53 samples from 40 noninfected children were IgA-negative. Statistical analysis was assessed comparing IgA results with HIV infection status as the gold standard. Sensitivity (95%) and specificity (100%), positive predictive value (100%), and negative predictive value (94%) of IgA antibody determination were analyzed taking into account only one sample per child and only children older than 6 months. Positive likelihood ratio was 95.9% and negative likelihood ratio was 94%. Test efficiency was 97%. The detection of IgA HIV antibodies using EIA is an effective method for early diagnosis of HIV-infected infants in comparison with conventional IgG HIV antibody tests. It is a simple and inexpensive method that could be used in both developed and developing countries.     

Serum cytokine levels in GH-deficient children during substitutive GH therapy

OBJECTIVE: The aim of the present study was to investigate the effect of exogenously administered human GH (hGH) on serum levels of interleukin (IL)-4, IL-6, IL-12 and tumour necrosis factor (TNF)-alpha in GH-deficient (GHD) children. DESIGN AND METHODS: We evaluated 13 short prepubertal GHD children, aged between 2 and 13 years, and 13 age-matched healthy subjects as controls. Circulating cytokine values were evaluated in basal conditions in all children, and 6 and 24 h following the 1st hGH injection (0.23 mg/kg per week), and then after 3 months of hGH treatment in GHD patients. Serum levels of IL-4, IL-6, IL-12 and TNF-alpha were measured by commercially available ELISAs. RESULTS: No significant differences were found between controls and GHD children in basal values of serum IL-4, IL-6, IL-12 and TNF-alpha (P > 0.05 by Mann-Whitney U test). Analysis of cytokine levels during hGH treatment showed significant changes over time in TNF-alpha and IL-6 levels (P = 0.0014 and P = 0.00 024 respectively), with the more pronounced effect observed at 6 h following the first administration of hGH (i.e. increase in IL-6 (Wilcoxon matched pairs test, P = 0.0015) and TNF-alpha levels (P = 0.0015)). No significant changes over time were observed in IL-4 and IL-12 serum levels. CONCLUSIONS: In vivo release of the pro-inflammatory cytokines IL-6 and TNF-alpha can be affected by hGH treatment in GHD children, suggesting a direct effect of GH on the immune function.     

我国HIV感染者HAART治疗后IPC水平变化的研究

目的探索我国艾滋病病毒(HIV)感染者外周血I型干扰素产生细胞(IPC)水平及高效抗逆转录病毒治疗(HAART)对IPC水平的影响。方法采用以BDCA2、BDCA4及CD4作为IPC特征性表面标志组合的全血染色法,对HIV阴性正常人、未接受HAART治疗的HIV感染者、接受3个月以上HAART治疗的HIV感染者的外周血样品IPC水平进行测定,使用SPSS 11.5 for Windows进行数据分析,比较两组间的差异使用Mann-Whitney Test检验。结果HIV感染者外周血中IPC水平明显低于正常人群;病毒载量(VL)低于检测下限(LDL)的感染者其IPC/CD4水平明显高于病毒载量大于LDL的感染人群;有效的HAART治疗后IPC及CD4的数量增加。结论IPC细胞在HIV感染中明显受损,有效的HAART治疗可以部分恢复IPC水平。     

HIV-induced, HIV-specific in vitro antibody response by B-cells from HIV-seropositive individuals.

OBJECTIVE: Recent studies have shown that B-cells from HIV-infected patients can secrete anti-HIV antibodies in vitro and that they represent 20-40% of immunoglobulin (Ig)-secreting B-cells in vivo. This study was designed to investigate the precise role of HIV in this in vitro antibody production. DESIGN AND METHODS: B-cells from HIV-infected patients [asymptomatic, n = 28; symptomatic (AIDS), n = 14], from seronegative adult volunteers (n = 22) and subjects at high risk for HIV infection (n = 15) were cultured in vitro in the presence of pokeweed mitogen, Staphylococcus aureus cowan or HIV, and T-cells or interleukins (IL). Non-specific Ig production and specific anti-HIV antibody (Ab) production were measured by enzyme-linked immunosorbent and Western blot assays. RESULTS: We found that HIV induced a specific response in cultured B-cells from seropositive patients, in contrast with cultured B-cells from uninfected normal individuals. The characteristics of the HIV-induced response differed from those of a spontaneous or a mitogen-induced response. Anti-HIV Ab production was optimal on day 8-10, when B-cells were cultured with recombinant IL-2 and recombinant interferon-alpha in the presence of infectious virus or recombinant gp160 Env protein. The anti-HIV Ab were mainly directed against Env proteins. Interaction of HIV with B-cells involved surface IgG but not CD4 antigen. Autologous CD8+ T-cells had a non-specific inhibitory effect. Both CD5+ and CD5- B-cells produced anti-HIV Ab. No anti-HIV Ab production was observed in B-cells from high-risk HIV-seronegative individuals. CONCLUSION: HIV (infectious virus or gp160) can induce B-cells from infected patients to secrete specific anti-HIV Ab in vitro.     

Reduced apoptosis in BALB/c mice infected with Heligmosomoides polygyrus

We evaluated levels of apoptosis and the immune response ex vivo in BALB/c mice infected with Heligmosomoides polygyrus. Cell proliferation, apoptosis and cytokine production were measured in mesenteric lymph nodes (MLN) without exposure to H. polygyrus antigens in culture. The inhibited apoptosis and cytokine production reported might reflect a state of cell hyporesponsiveness in the prepatent phase of infection. These changes were accompanied by changes in the percentage of CD4+ cells in MLN and popliteal lymph nodes (PLN). The prolonged reduction in apoptosis coexisted with induced cell proliferation, elevated TNF-alpha, IL-12p70, IFN-gamma, IL-6, IL-10 and TGF-beta synthesis, but lowered IL-4 and IL-2 levels. In the chronic phase of infection an increasing production of IFN-gamma, monocyte chemotactic protein-1 (MCP-1), IL-10 and TGF-beta with decreasing concentrations of other cytokines resulted in restored apoptosis. The cytokine response in serum showed moderate production of TNF-alpha, temporary involvement of IL-12p70, induction of IFN-gamma and IL-10 synthesis, as well as growing IL-6 and MCP-1 production. It is suggested that a synchronized synthesis of distinct cytokines is accompanied by different levels of inhibited apoptosis during the prepatent and chronic phases of H. polygyrus infection in BALB/c mice. We suggest that immunosuppression provoked by the nematode is not the outcome of parasite-induced apoptosis, but rather results from a hyporesponsiveness experienced by cells during H. polygyrus infection.     

Differential regulation of proinflammatory and hematopoietic cytokines in human macrophages after infection with human immunodeficiency virus

Cells of the macrophage lineage (MAC) play an important role in human immunodeficiency virus (HIV) infection. However, the knowledge on the extent of macrophage involvement in the pathogenesis of HIV infection is still incomplete. In this study we examined the secretory repertoire of HIV-infected MAC with respect to the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL- 6, IL-8, and the hematopoietic growth factors M-, G- and granulocyte- macrophage colony stimulating factor (GM-CSF). Using a culture system on hydrophobic teflon membranes, blood-derived MO from healthy donors were infected with a monocytotropic HIV-1 isolate (HIV-1D117IIII). We analyzed the constitutive and lipopolysaccharides-stimulated secretion of MO/MAC early after infection as well as in long-term cultured, virus- replicating cells. The release of proinflammatory mediators and hematopoietic growth factors were differentially regulated after infection with HIV: the secretion of TNF-alpha, IL-1 beta, IL-6, IL-8 was upregulated, whereas a down-regulation of M-, G-, and GM-CSF could be observed. These results may provide some explanation for the immunological dysfunction, the hematopoietic failure and the chronic inflammatory disease occurring in HIV-infected patients.     

Evaluation of serum cytokine concentrations in patients with infective endocarditis

BACKGROUND AND AIM OF THE STUDY: Early diagnosis of infective endocarditis is important for clinical outcome, as mortality increases if diagnosis is delayed. Diagnosis is based on clinical features, echocardiography and blood culture findings, but negative blood cultures have been reported in 5-15% of proven cases. The study aim was to investigate serum cytokine levels in patients with infective endocarditis, and the possible use of these data in diagnosis and monitoring of the disease. METHODS: The study group comprised 40 patients with acquired rheumatic valvular heart disease and ongoing infective endocarditis. A diagnosis of infective endocarditis was established by clinical examination, echocardiography, laboratory investigations (inflammatory parameters) and positive blood cultures (n = 34). Two control groups included patients with acquired rheumatic valvular heart disease: 15 without infective endocarditis, and 15 with active urinary tract infection with significant bacteriuria. Serum interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were measured on three occasions during antimicrobial treatment (mean period 14 +/- 7 days). RESULTS: Serum IL-1alpha and TNF-alpha levels were not elevated in the study group, or in controls (IL-1alpha <3.9 pg/ml; TNF-alpha <10 pg/ml). Serum IL-6 levels were elevated on all occasions in patients with infective endocarditis (first measurement: 37.0 +/- 44.3 pg/ml; second 18.7 +/- 16.4; third 8.5 +/- 5.2) with a significant tendency to decrease during treatment (p <0.01, ANOVA). In all controls without infection the serum IL-6 concentrations were below calibration range (<3.2 pg/ml). In the control group with active urinary tract infection, IL-6 concentrations were slightly (but not significantly) elevated (4.49 +/- 1.82 pg/ml, p = NS). CONCLUSION: Elevated serum IL-6 levels may suggest ongoing infective endocarditis and might be used to aid in diagnosis and monitoring of treatment of the disease. Serum IL-1alpha and TNF-alpha levels were not affected. A further understanding of the role of serum cytokine concentrations in the diagnosis, prognosis and monitoring of infective endocarditis might be valuable in clinically uncertain diagnoses, especially when blood cultures are negative.     

Enhanced production of tumor necrosis factor-alpha and interleukin-6 due to prolonged response to lipopolysaccharide in human macrophages infected in vitro with human immunodeficiency virus type 1

Elevated levels of circulating tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 have been detected in human immunodeficiency virus (HIV) type 1 infection. The overproduction of these cytokines could contribute to AIDS pathogenesis. Thus, the expression of TNF-alpha and IL-6 in human macrophages infected with HIV-1 was investigated. HIV-1 infection, per se, did not induce any TNF-alpha or IL-6 production or cytokine-specific mRNA expression. In contrast, HIV-1 primed macrophages to a prolonged TNF-alpha and IL-6 response to lipopolysaccharide (LPS) stimulation with respect to uninfected cells. Time-course analysis and flow cytometry demonstrated that cytokine production stopped at 6 h in uninfected macrophages but continued up to 24 h in HIV-1-infected cells. RNA studies suggested that HIV-1 interfered with late steps of cytokine synthesis. No modulation of membrane CD14 was found to account for the enhanced response to LPS. Finally, the effect of HIV-1 on cytokine response could not be abolished by the antiviral compound U75875.     

Effect of specific immunotherapy on serum levels of tumor necrosis factor alpha in asthmatic children.

There is no general agreement among investigators regarding the effect of specific immunotherapy (SIT) on T-cell reactivity. The aim of this study was to investigate the serum levels of IL-1beta, IL-6, and TNF-alpha of children with allergic asthma before and after 3 and 12 months of SIT. Additionally, after 12 months of SIT, we investigated the bronchial hyperresponsiveness. The secondary end points were clinical parameters. Thirty-two children with moderate asthma allergic to house-dust mites (study group) and 10 healthy children (control group) participated in this trial. At each visit blood samples were drawn from all asthmatic patients and at the prestudy visit in controls for determination of parameters. All asthmatic patients received SIT. At the second study visit, baseline spirometry and methacholine challenge tests were performed. Serum TNF-alpha during SIT tended to increase after 3 months with respect to baseline, whereas after 12 months of SIT, serum TNF-alpha decreased. The correlation coefficient (r) between the changes in TNF-alpha values between 3 and 12 months of SIT and provocative concentrations of methacholine to cause a 20% fall in FEV(1) (PC20M) after 12 months of SIT was positive (r = 0.76; p < 0.0001); the greater the changes in TNF-alpha level, the higher the PC20. No modification of IL-1beta and IL-6 was observed. Clinical symptoms also improved after 12 months of SIT in children with asthma. In summary, our results showed the variations in serum levels of TNF-alpha during SIT in asthmatic children and confirm anti-inflammatory properties of SIT.     

Effect of plasma exchange on serum tissue inhibitor of metalloproteinase 1 and cytokine concentrations in patients with fulminant hepatitis

AIMS: The present study assessed whether the serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and cytokines are altered in patients with fulminant hepatitis and whether plasma exchange affects these concentrations. METHODS: Fifteen patients with fulminant hepatitis, 14 patients with severe acute hepatitis, and 20 healthy controls were included in this study. The serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), transforming growth factor beta (TGF-beta), and TIMP-1 were determined in all patients upon hospital admission and before and after a single course of plasma exchange in the patients with fulminant hepatitis. RESULTS: Ten out of the 15 patients with fulminant hepatitis and all patients with severe acute hepatitis survived. Serum TNF-alpha, IL-6, TGF-beta, and TIMP-1 levels in patients with fulminant hepatitis were significantly higher than the levels in patients with severe acute hepatitis (p < 0.01). IL-1beta was not detectable in either group. Plasma exchange reduced the increased serum concentrations of TNF-alpha, IL-6, TGF-beta, and TIMP-1 in patients with fulminant hepatitis (p < 0.01). CONCLUSIONS: These data suggest that increased serum levels of TIMP-1 and cytokines may reflect severe hepatic inflammation and that plasma exchange is an effective therapy to reduce these levels.     

Serum concentrations of the CXC chemokines interleukin 8 and growth-regulated oncogene-alpha are elevated in patients with systemic sclerosis

OBJECTIVE: To determine whether serum concentrations of 2 CXC chemokines, interleukin 8 (IL-8) and growth-regulated oncogene-alpha (GRO-alpha), which are potent chemoattractants and activators for neutrophils, are elevated and whether they correlate with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 36), limited cutaneous SSc (lSSc; n = 42), systemic lupus erythematosus (SLE; n = 15), dermatomyositis (DM; n = 15), and healthy controls (n = 35) were examined by ELISA. RESULTS: Serum IL-8 was detected significantly more frequently in patients with dSSc (61%) and lSSc (55%) relative to healthy controls (6%), patients with SLE (7%), and those with DM (13%). Similarly, serum GRO-alpha concentrations in SSc patients were significantly increased compared with controls, patients with SLE, or those with DM. Elevated IL-8 concentrations significantly correlated with decreased % DLCO and rheumatoid factor positivity, while increased GRO-alpha levels were significantly associated with decreased % DLCO and % vital capacity, involvement of kidney and muscle, the presence of anti-topoisomerase I antibody, and increased serum IgG levels. CONCLUSION: Our results suggest that the elevation of serum levels of the CXC chemokines IL-8 and GRO-alpha is specific to SSc and that the elevation of CXC chemokines, particularly GRO-alpha, correlates with the involvement of internal organs, especially pulmonary damage.