Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma

Allergen-reactive T helper type-2 (Th2) cells and proinflammatory cytokines have been suggested to play an important role in the induction and maintenance of the inflammatory cascade in allergic asthma. We compared the plasma concentrations of novel proinflammatory cytokines IL-17 and IL-18, other proinflammatory cytokines IL-6 and IL-12, Th2 cytokines IL-10 and IL-13, and intracellular interferon-gamma (IFN-gamma) and IL-4 in Th cells of 41 allergic asthmatics and 30 sex- and age-matched health control subjects. Plasma cytokines were measured by enzyme-linked immunosorbent assay. Intracellular cytokines were quantified by flow cytometry. Plasma IL-18, IL-12, IL-10, IL-13 concentrations were significantly higher in allergic asthmatic patients than normal control subjects (IL-18: median 228.35 versus 138.72 pg/ml, P < 0.001; IL-12: 0.00 versus 0.00 pg/ml, P = 0.001; IL-10: 2.51 versus 0.05 pg/ml, P < 0.034; IL-13: 119.38 versus 17.89 pg/ml, P < 0.001). Allergic asthmatic patients showed higher plasma IL-17 and IL-6 concentrations than normal controls (22.40 versus 11.86 pg/ml and 3.42 versus 0.61 pg/ml, respectively), although the differences were not statistically significant (P = 0.077 and 0.053, respectively). The percentage of IFN-gamma-producing Th cells was significantly higher in normal control subjects than asthmatic patients (23.46 versus 5.72%, P < 0.001) but the percentage of IL-4 producing Th cells did not differ (0.72 versus 0.79%, P > 0.05). Consequently, the Th1/Th2 cell ratio was significantly higher in normal subjects than asthmatic patients (29.6 versus 8.38%, P < 0.001). We propose that allergic asthma is characterized by an elevation of both proinflammatory and Th2 cytokines. The significantly lower ratio of Th1/Th2 cells confirms a predominance of Th2 cells response in allergic asthma.     

The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the Th2 type

Most cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection have a persistent acute type lung inflammation dominated by polymorphonuclear neutrophils (PMN) and a pronounced antibody response against P. aeruginosa. We speculated whether this immune response in CF is of the Th2 type and whether a change to a Th1 type immune response could improve the prognosis. Therefore, we studied 14 CF patients with (CF +P) and 14 CF patients without (CF -P) chronic P. aeruginosa lung infection. The specific production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by peripheral blood mononuclear cells was determined. Cells from CF +P patients had lower IFN-gamma (p<0.05) and higher IL-4 (p<0.005) production as compared to cells from CF -P patients. Furthermore, a positive correlation between IFN-gamma production and lung function was found (FVC: Rho = 0.637; p<0.03; FEV1: Rho=0.524; p<0.07). We conclude that a Th2 type immune response is most frequent in CF patients with chronic P. aeruginosa lung infection, and the patients with a Th1-dominated immune response had the best lung function. The clinical implication is that a change to a Th1 type immune response might improve the prognosis in these patients.     

苦参素对HBsAg转基因小鼠血清Th1和Th2细胞因子水平的影响

目的　探讨苦参素对HBsAg转基因小鼠外周血Th1 Th2细胞因子水平的影响。方法　HBsAg转基因小鼠分成苦参素组和对照组 ,分别每天腹腔注射苦参素注射液 2 0 0mg kg 0 2ml和生理盐水 0 2ml,共 30d。处理前后 ,检测外周血清细胞因子水平。结果　对照组处理前后γ 干扰素(IFN γ)与白细胞介素 4 (IL 4 )水平差异无显著意义 ;苦参素组处理前后IFN γ分别为 (3 10 8± 3 172 )pg ml和 (11 0 5 9± 6 971)pg ml,IL 4分别为 (2 9 0 4 5± 13 2 35 )pg ml和 (13 0 2 4± 9 0 0 2 )pg ml(均P <0 0 0 1)。处理后对照组与苦参素组IL 2分别为 (1 0 70± 0 4 4 7)pg ml和 (5 5 37± 2 887)pg ml(P <0 0 0 0 1) ;IL 10分别为 (97 2 2 6± 73 30 6 )pg ml和 (33 6 0 7± 2 3 15 4 )pg ml(P <0 0 1)。结论　在苦参素作用后 ,HBsAg转基因小鼠体内的Th1型细胞因子明显升高 ,Th2型细胞因子明显降低。这将有助于研究苦参素临床治疗乙型肝炎的机制。     

Serum cytokine levels and antibody response to influenza vaccine in the elderly

Cytokines play critical roles in regulating the antibody response to vaccines. We sought to understand the role of endogenous cytokines in the determination of antibody production in the elderly, a group of subjects known to have a lower response rate to vaccination. We found that in a healthy elderly group, only 52% of whom responded to the influenza vaccine, endogenous levels of interleukin 6 (IL-6), IL-10 and gamma interferon (IFNgamma) did not differ statistically significantly between responders and non-responders (responders: n = 27, IL-6 = 293 +/- 101 pg/ml, IL-10 = 882 +/- 240 pg/ml; nonresponders: n = 26, IL-6 = 223 +/- 71 pg/ml, P = 0.57, IL-10 = 445 +/- 148 pg/ml, mean +/- SE, P = 0.14, respectively, and undetectable IFNgamma). Serum levels of these three cytokines were not changed significantly four weeks after vaccination (P < 0.05 for IL-6 and P < 0.01 for IL-10). In addition, there were also no age-dependent differences in serum IL-6 and IL-10 levels.     

Serum concentrations of GM-CSF and G-CSF correlate with the Th1/Th2 cytokine response in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection

The inflammation in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection is dominated by polymorphonuclear neutrophils (PMNs). There seems to be a relationship between the PMN-dominated inflammation, pronounced antibody production and a Th2-dominated response. Apart from mobilizing monocytes and PMNs from the bone marrow, GM-CSF, G-CSF and IL-3 select subsets of dendritic cells, which subsequently induce distinct Th responses. Therefore, the present study examines the correlation between the mobilizing cytokines in serum and the Th responses. The IFN-gamma and IL-4 production by peripheral blood mononuclear cells, and the concentrations of GM-CSF and G-CSF in serum as well as lung function, were determined in 37 CF patients with and 6 CF patients without chronic P. aeruginosa lung infection. The GM-CSF/G-CSF ratio correlated both with the IFN-gamma production and good lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment.     

Early immune response in susceptible and resistant mice strains with chronic Pseudomonas aeruginosa lung infection determines the type of T-helper cell response

Most cystic fibrosis (CF) patients become chronically infected with Pseudomonas aeruginosa in the lungs. The infection is characterized by a pronounced antibody response and a persistant inflammation dominated by polymorphonuclear neutrophils. Moreover a high antibody response correlates with a poor prognosis. We speculated that a change from this Th2-like response to a Th1-like response might decrease the lung inflammation and thus improve the prognosis in CF patients. To investigate this, we infected C3H/HeN and BALB/c mice intratracheally with P. aeruginosa. In addition, we studied the early immune response leading to different Th responses. Mortality was lower in the C3H/HeN mice (p<0.005), they cleared the bacteria faster (day 3 p<0.01, day 7 p<0.02), had a milder lung inflammation (day 7 p<0.01, day 14 p< or =0.0005) and had a Th1-like IgG subclass switch. At day 3, the C3H/HeN mice produced less NO and TNF-alpha, (p<0.01 and p<0.03) and had the lowest IL-10/IL-12 ratio (p< or =0.05). At day 7, the C3H/HeN mice had the highest IFN-gamma (p<0.02), and the lowest IL-4 (p<0.02) production in the lungs. In conclusion, these results show that the Th1-reacting C3H/HeN mice with chronic P. aeruginosa lung infection have a better disease outcome compared to the Th2-reacting BALB/c mice, indicating that a Th1 response might be beneficial in CF patients with chronic P. aeruginosa lung infection.     

Th2-type cytokines modulate IL-6 release by human bronchial epithelial cells

The multifunctional cytokine IL-6, which can be locally produced by human bronchial epithelial cells (HBECs), has been found to play a role in IL-4 dependent IgE synthesis. Since the allergic reaction in bronchial asthma is associated with the upregulation of IL-4 and Th2 type of immune response, the purpose of our study was to assess whether IL-4 and related cytokines IL-10 and IL-13 regulate IL-6 release by HBEC s. HBECs were obtained by bronchial brushing, cultured in LHC-9/RPMI 1640. At the third passage the cells were stimulated with cytokines (0.1-20 ng/ml) diluted in unsupplemented media for 24 h. The supernatants were tested for IL-6 content by sandwich ELISA. Unstimulated HBECs produced detectable amounts of IL-6 (368+/-25 pg/ml). Exposure to IL-10 (368+/-22 pg/ml) and IL-13 (395+/-6 pg/ml) resulted in little changes. IL-4 caused a slight but significant increase in IL-6 release (530+/-45 pg/ml), P<0.05, TNFalpha (1657+/-85 pg/ml) and IFNgamma (1953+/-37 pg/ml) showed strong induction of IL-6 release in HBECs (P<0.005 and P<0.001, respectively). Both IL-4 and IL-13 significantly inhibited TNF induced IL-6 release (P<0.01 for both) while augmenting the effect of IFNgamma (P<0.005 and P<0.01, respectively.). IL-10 was without a significant effect. We conclude that Th2-type cytokines IL-4 and IL-13 affect the release of IL-6 by HBECs in response to TNFalpha (inhibition) and IFgamma (augmentation). IL-10 had no effect on the regulation of IL-6 release. Modulation of IL-6 levels by Th2-type cytokines may play a role in allergic reactions through the IL-6 promoting effect on IL-4 mediated IgE production.     

In vitro production of cytokines by peripheral blood mononuclear cells from hydatid patients.

The role of cytokines in human hydatidosis (Echinococcus granulosus infection) was evaluated in immunoassays determining production of IL-4, IL-10 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cell (PBMC) cultures from 30 hydatid patients and 14 uninfected controls. In cell cultures from hydatid patients parasite and non-parasite antigen stimulation significantly increased IL-4 production (P < or 0.005). Spontaneous and mitogen-driven IL-4 production was similar in patients and controls. IL-10 and IFN-gamma production did not differ statistically in the two groups, even though some hydatid patients produced these cytokines in large amounts. Notably, antigen-driven IFN-gamma concentrations were invariably higher in patients than in uninfected controls. Data analysis showed a relationship between IgE and IgG4 responses and parasite-driven cytokine production. High IgE and IgG4 responders produced high IL-4 and IL-10 concentrations. High IgE responders showed decreased IFN-gamma production, but high IgG4 responders had IFN-gamma levels slightly higher than those of low responders. Cytokine response patterns did not relate to the clinical stage of disease. The significantly increased IL-4 and the high IL-10 concentrations found in PBMC from many hydatid patients in this study are consistent with Th2 cell activation in human hydatidosis. The presence of antigen-driven IFN-gamma production in patients with E. granulosus infection implies concurrent intervention of the Th1 or Th0 cell subset.     

Implantation: Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients

This study was undertaken to investigate an empirical observationthat ‘high responder patients have poorer in-vitro fertilization(IVF) outcome than normal responder patients’. The aimof our study was to analyse the effect of high serum oestradioland progesterone concentrations at the day of human chorionicgonadotrophin (HCG) administration on endometrial receptivityand oocyte—embryo quality in high and normal responderpatients. The IVF patients were divided into two groups: 59high responder patients who voluntarily donated some of theiroocytes, and a control group consisting of 105 normal responderpatients. Both groups were compared in terms of the number andquality of oocytes retrieved, embryos transferred, fertilization,implantation and gestation rates, serum oestradiol and progesteroneconcentrations and the oestradiol: progesterone ratio on theday of HCG injection. To ascertain oocyte—embryo quality,a second control group of 96 women undergoing oocyte donation(receiving oocytes from high responder patients) was considered.To assess the impact of steroid concentrations on endometrialreceptivity, high responder patients were divided into two subgroupsaccording to oestradiol concentration, above or below the minimaloestradiol and progesterone concentrations (mean – SD)in this group. The normal responder patients were divided intotwo subgroups according to oestradiol concentration, above orbelow the maximal oestradiol and progesterone concentrations(mean + SD) in this group. To assess further the relevance ofoestradiol concentration on endometrial receptivity, patientswere divided into different subgroups according to increasingoestradiol concentration, regardless of whether they were highor normal responders. High responder patients had significantlydecreased implantation and pregnancy rates per cycle comparedwith normal responder patients (33.3 versus 16.3 and 11.1 versus5.4% respectively; P < 0.05). The results of 108 embryo transfersin 91 recipients who received oocytes from the high respondergroup showed normal embryo quality. Implantation rates and pregnanciesper cycle were significantly lower in high responder patientswith serum oestradiol concentrations > 1700 pg/ml comparedwith those having oestradiol concentrations 1700 pg/ml, as wellas in normal responder patients with serum oestradiol concentrations2200 pg/ml compared with those having oestradiol concentrations<2200 pg/ml. Considering all the patients together, significantdecreases in pregnancy and implantation rates were observedwhen oestradiol concentrations were >2500 pg/ml comparedwith patients having lower oestradiol concentrations. Our clinicalresults demonstrate that high serum oestradiol concentrationson the day of HCG injection in high and normal responder patients,regardless of the number of oocytes retrieved and the serumprogesterone concentration, are detrimental to uterine receptivitywithout affecting embryo quality.     

IL-23在慢性乙型肝炎免疫调节中的作用研究

目的 探讨IL-23在慢性乙型肝炎免疫调节中的作用。方法 选取我院收治的32例HBeAg阳性慢性乙型肝炎患者为研究对象,根据ALT水平分为ALT≥120 IU/ml患者16例,ALT＜120 IU/ml患者16例,另外选择我院健康体检中心20例体检者作为健康对照组,采用酶联免疫分析法（ELISA）检测血清IL-23水平,采用流式细胞仪检测Th17细胞百分率。结果 与健康对照组相比,HBeAg阳性慢性乙型肝炎患者血清IL-23表达及外周血Th17细胞百分率均升高,差异有统计学意义（P＜0.05）; ALT≥120 IU/ml患者血清IL-23浓度（394.81±101.84）pg/ml高于ALT＜120IU/ml的（283.69±85.65）pg/ml,ALT≥120 IU/ml患者Th17细胞百分率（3.25±0.70）%高于ALT＜120IU/ml的（2.68±0.61）%,差异均有统计学意义（P＜0.05）;慢性乙型肝炎患者外周血Th17细胞百分率、血清IL-23浓度与ALT程度呈正相关（P均＜0.05）;Th17细胞百分率与血清IL-23浓度呈正相关（P＜0.05）。结论 IL-23可能通过影响Th17细胞的免疫调节参与慢性乙型肝炎患者炎症,为临床提供了新的靶标。     

Role of Th1 and Th2 cytokines in immune response to uncomplicated Plasmodium falciparum malaria

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-gamma), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-gamma, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 +/- 2.8 pg/ml; controls, 3.2 +/- 0.7 pg/ml) and IFN-gamma (39.2 +/- 67.6 pg/ml; controls, 8.4 +/- 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 +/- 2.6 pg/ml), whereas IFN-gamma levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 +/- 200.4 pg/ml and 56.6 +/- 38.4 pg/ml, respectively; controls, 17.4 +/- 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 +/- 1.2 pg/ml; controls, 2.4 +/- 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 +/- 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-gamma levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-gamma may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.     

Improved outcome of chronic Pseudomonas aeruginosa lung infection is associated with induction of a Th1-dominated cytokine response

Repeated challenge with antigen is involved in the pathogenesis of a variety of pulmonary diseases. Patients with cystic fibrosis (CF) experience recurrent pulmonary colonization with Pseudomonas aeruginosa before establishment of chronic lung infection. To mimic recurrent lung infections in CF patients, the lungs of susceptible BALB/c mice were re-infected with P. aeruginosa 14 days after the initial infection. Singly-infected BALB/c mice, as well as non-infected mice, were used as controls. Decreased mortality and milder lung inflammation in re-infected BALB/c mice, as well as a tendency for improved clearance of bacteria, was observed when compared with singly-infected mice. The improved outcome in re-infected mice correlated with changes in CD4 cell numbers. Surface expression of LFA-1 on pulmonary CD4 cells was increased in re-infected compared with singly-infected mice. Moreover, resistance to re-infection was paralleled by a shift towards a Th1-dominated response and increased IL-12 production. No significant increase in serum IgG was observed in the re-infected mice. In conclusion, these results indicate a protective role for a Th1-dominated response, independent of antibody production, in chronic P. aeruginosa lung infection in CF.     

Intravenous immunoglobulin treatment in women with recurrent abortions: increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood

PROBLEM: The aim of this study was to investigate changes in peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios after massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology. METHOD OF STUDY: Serum Th1 (IFN-gamma, TNF-alpha) and Th2 cytokine (IL-4, IL-10) levels were assessed by ELISA methods (n = 9) and peripheral blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before and after MIVIg treatments in women with four or more consecutive RSA. RESULTS: Pre-treatment serum IFN-gamma (0.06 +/- 0.09 pg/mL, mean +/- SD), TNF-alpha (0.21 +/- 0.45 pg/mL), IL-4 (0.70 +/- 1.16 pg/mL), and IL-10 (1.12 +/- 1.67 pg/mL) increased to 0.17 +/- 0.16 pg/mL, 0.77 +/- 0.28 pg/mL, 1.82 +/- 0.89 pg/mL, and 3.44 +/- 0.48 pg/mL, respectively, after MIVIg treatments (P < 0.05). CD4-positive IFN-gamma/IL-4 lymphocyte ratios (17.3 +/- 9.1) were reduced to 11.5 +/- 7.1 after treatment (P < 0.05). CONCLUSIONS: Massive intravenous immunoglobulin treatments increased peripheral blood cytokine levels and decreased Th1/Th2 lymphocyte ratios; thus, MIVIg treatments modify the peripheral Th1/Th2 balance.     

腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡的影响

目的:为了探讨腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡的影响。方法:择期子宫肌瘤患者4 0例,分别采用腹腔镜手术和常规开腹手术,测定术前、术后2、2 4、4 8小时Th1、Th2细胞数量及血清IL 18、IL 10水平。结果:两组术后2小时均出现Th1/Th2细胞平衡向Th2反应转换,Th1细胞、Th1/Th2比值、IL 18下降(腹腔镜组:P <0 0 5 ,P <0 0 1,P <0 0 5 ;开腹组:P <0 0 1,P <0 0 1,P <0 0 1) ,而Th2细胞、抗炎因子IL 10上升(腹腔镜组:P <0 0 1,P <0 0 1;开腹组:P <0 0 1,P <0 0 1)。但腹腔镜组术后2 4小时各项指标即恢复,而开腹组各项指标的变化与术后2小时类似,并持续至术后4 8小时。结论:腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡影响小,恢复快,优于开腹手术。     

CD4(+)IL-13(+) cells in peripheral blood well correlates with the severity of atopic dermatitis in children

BACKGROUND: In atopic dermatitis (AD) a Th1/Th2 imbalance has been reported, and interleukin (IL)-13 seems to play a pivotal role in the inflammatory network. We tried to assess the correlation between the immunological marker CD4(+)IL-13(+) and the clinical phase of extrinsic AD in children. METHODS: Twenty children with AD were studied. Assessed parameters were: clinical severity (SCORAD index), total serum immunoglobulin E (IgE), blood eosinophil count, and percentage of CD4(+)IFNgamma(+), CD4(+)IL-4(+), CD4(+)IL-13(+) T cells. Determinations were carried out in the acute phase and after clinical remission were achieved. Ten nonatopic-matched children served as controls. RESULTS: At baseline, AD was mild in 25%, moderate in 50% and severe in 25% of children. In the acute phase a significant relationship between the eosinophil count and the SCORAD index was found (P = 0.0001). Blood CD4(+)IL-4(+) were significantly higher in the AD group (median 17.0, range: 13.7-21.4) than in controls (12.6, 6.4-17.2, P < 0.0001). CD4(+)IL-13(+) cells in the AD group well correlated (P = 0.0007) with SCORAD index. At remission, a significant correlation between SCORAD index and eosinophil count was found (P < 0.03) and the percentage of CD4(+)IL-13(+) cells globally decreased (P < 0.0001), while no difference was found among SCORAD classes. CONCLUSION: This study confirms the Th2 profile predominance in the peripheral blood of children with AD, and evidences close relationship between the number of CD4(+)IL-13(+) T cells and the disease's severity.     

Cytokine production in NOD mice on prophylactic insulin therapy

We investigated whether cytokines produced primarily by monocytes/macrophages (IL-1alpha), Th1-lymphocytes (IFNgamma), or Th2-lymphocytes (IL-4) are modulated in diabetes-prone NOD mice by insulin treatment as used in prophylaxis studies. The cytokines were measured by ELISA in plasma and in supernatants of spleen cells activated ex vivo by lipopolysaccharide plus phytohemagglutinin. Insulin, 0.25-0.50 IU/day, was given subcutaneously for 8 weeks starting in 4-week-old female mice. The insulin-treated and control NOD mice showed similar weight gains and, by the end of the study, both groups exhibited cell infiltration in about 25% of their islets. IL-1alpha, IFNgamma and IL-4 were generally below detection in plasma of prediabetic animals and controls. Diabetic NOD mice, aged 28-45 weeks, had significantly elevated plasma IL-1alpha: 154+/-39 pg/ml (mean+/-SEM, p<0.0001). While ex vivo activated NOD splenocytes released similar amounts of IL-1alpha, insulin therapy increased the levels from 99+/-17 to 155+/-19 pg/10(6) cells (p<0.05). Supernatants of activated splenocytes from prediabetic NOD mice had lower levels of IL-4 (<15 pg/10(6) cells) compared with those from BALB/c mice (88+/-22 pg/10(6) cells; p<0.01), and this deficiency was partially compensated for when the NOD mice were given insulin (27+/-8; p<0.01). The levels of IFNgamma were comparable and largely unaffected by insulin treatment. Hence, insulin therapy appears to partially normalize an otherwise deficient Th2 response in NOD mice.     

Enhanced interleukin-18 levels in the peripheral blood of children with coeliac disease

Coeliac disease (CoD) is a small intestinal disorder characterized by villous atrophy, crypt cell hyperplasia and an increased production of T helper cell type 1 (Th1) cytokines. Interleukin (IL)-18 is a pro-inflammatory cytokine that has a crucial role in maintaining the Th1 response. In this study, the serum levels of IL-18 were measured in children with CoD or other gastrointestinal diseases in order to evaluate the possibility of using IL-18 as a disease activity marker. IL-18 levels were higher in samples from CoD patients [median 443 pg/ml (148-885)] compared to healthy controls [median 205 pg/ml (11-379)], P <0.05. In contrast, the levels of IL-18 were not enhanced significantly in the serum from patients with inflammatory bowel disease (IBD) [median 324 pg/ml (207-546)] or in the disease control group [median 303 pg/ml (2-689)]. In CoD patients, after 2 weeks of gluten challenge (GC), serum IL-18 was unchanged [median 268 pg/ml (59-458)] compared to patients on a gluten-free diet [median 220 pg/ml (53-600)], while IL-18 was increased after 12 weeks of GC [median 551 pg/ml (94-952)], P <0.01. The IL-18 levels correlated with IgA anti-transglutaminase antibody levels (rs=0.59, P=0.016) in serum from untreated CoD patients, and IL-18 also followed the degree of small intestinal villous atrophy in 12 out of 19 CoD patients. Our results support the view that serum IL-18 concentrations in children with CoD follow disease activity, suggesting a role for IL-18 in the induction of an inflammatory Th1-response after gluten exposure.     

Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-γ), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-γ, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 ± 2.8 pg/ml; controls, 3.2 ± 0.7 pg/ml) and IFN-γ (39.2 ± 67.6 pg/ml; controls, 8.4 ± 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 ± 2.6 pg/ml), whereas IFN-γ levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 ± 200.4 pg/ml and 56.6 ± 38.4 pg/ml, respectively; controls, 17.4 ± 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 ± 1.2 pg/ml; controls, 2.4 ± 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 ± 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-γ levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-γ may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.     

Dietary omega-3 polyunsaturated fatty acids from fish oil reduce interleukin-12 and interferon-gamma production in mice

The objective of this study was to investigate the impact of feeding mice a diet rich in n-3 polyunsaturated fatty acids (PUFA) from fish oil on the interleukin-12 (IL-12) and interferon-gamma (IFNgamma) production during the early stage of an infectious challenge with Listeria monocytogenes. Weanling female C3H/HeN mice were fed AIN-93G experimental diets containing 20%, by weight one of three fat sources: lard (low PUFA), soybean oil (n-6 PUFA) or a mixture (9:1) of menhaden fish oil and corn oil (n-3 PUFA). After 4 weeks, mice were injected intraperitoneally with 10(5) Listeria monocytogenes and the concentration of IL-12(p70) and IFNgamma in serum was determined 24 h post-infection by ELISA. IL-12p35, IL-12p40 mRNA, and IFNgamma mRNA in the spleen were quantified by RNase protection assay. The number of IFNgamma-producing cells in the spleen was determined by flow cytometry using an intracellular staining procedure. We found that n-3 PUFA-fed mice had lower levels of circulating IL-12 at 24 h post-infection than n-6 PUFA- or low PUFA-fed mice (9.7+/-3.4 pg/ml vs. 61.6+/-10.6, and 44.4+/-12.5 pg/ml, respectively; P=0.002, n = 10/trt). The level of IL-12 p35 mRNA did not significantly differ among dietary treatment groups. However, IL-12p40 mRNA was significantly lower in n-3 PUFA- and n-6 PUFA-fed mice compared to low-PUFA-fed mice. Further, the n-3 PUFA group also had the lowest circulating IFNgamma (4.4+/-1.8 ng/ml vs. 9.1+/-1.0, and 9.7+/-2.1 ng/ml, respectively; P = 0.007. n = 8-10/trt). The n-3 PUFA-fed mice had significantly lower IFNgamma mRNA in their spleens compared to the mice fed the other fat sources. In agreement with having lower circulating IFNgamma and lower splenic IFNgamma mRNA, n-3 PUFA-fed mice had a significantly lower percentage of IFNgamma-producing cells in their spleens compared with the n-6 PUFA-fed group (2.1+/-0.6 vs. 4.2+/-0.7%; P = 0.037, n = 10/trt). In summary, feeding mice a diet rich in n-3 PUFA from fish oil significantly lowered the production of both IL-12 and IFNgamma during the early phase of a Listeria infection.