Chun Kwok Wong

Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity.

IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p<0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p<0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p<0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p<0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.

Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation.

Leptin is a pleiotropic adipocyte‐derived cytokine used in hypothalamic regulation of body weight and modulation of immune response by stimulating T cells, macrophages and neutrophils. Leptin has been shown to be an eosinophil survival factor. We examined the immunopathological mechanisms for the activation of human eosinophils from healthy volunteers by leptin in allergic inflammation. Adhesion molecules, cytokines and cell migration were assessed by flow cytometry, ELISA and Boyden chamber assay, respectively. Intracellular signaling molecules were investigated by membrane array and Western blot. Leptin could up‐regulate cell surface expression of adhesion molecule ICAM‐1 and CD18 but suppress ICAM‐3 and L‐selectin on eosinophils. Leptin could also stimulate the chemokinesis of eosinophils, and induce the release of inflammatory cytokines IL‐1β and IL‐6, and chemokines IL‐8, growth‐related oncogene‐α and MCP‐1. We found that leptin‐mediated induction of adhesion molecules, release of cytokines and chemokines, and chemokinesis were differentially regulated by the activation of ERK, p38 MAPK and NF‐κB. In view of the above results and elevated production of leptin in patients with allergic diseases such as atopic asthma and atopic dermatitis, leptin could play crucial immunopathophysiological roles in allergic inflammation by activation of eosinophils via differential intracellular signaling cascades.

Tumor necrosis factor-α up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways

Both circulating and urinary tumor necrosis factor (TNF)-alpha levels have been shown to increase in inflammatory chronic kidney diseases and TNF-alpha can induce secretion of other inflammatory mediators from many cell types. Chemokine, mononuclear chemoattractant protein-1 (CCL2/MCP-1), and cell surface adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), in renal proximal tubular epithelial cells (PTEC) are important for promoting recruitment and adhesion of infiltrating macrophages and lymphocytes to inflamed renal tissue. This study aimed to investigate the effect of TNF-alpha on the expression of these inflammation-related molecules of human PTEC and the underlying intracellular mitogen-activated protein kinase (MAPK) regulatory signaling mechanisms. Cytokine expression profile of TNF-alpha-activated PTEC was assayed by protein array. The concentration of CCL2 was analyzed by ELISA, while the expression of cell surface ICAM-1 and VCAM-1 and intracellular phosphorylated p38 MAPK, c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was assessed using flow cytometry. TNF-alpha could significantly induce CCL2, ICAM-1 and VCAM-1 expression of PTEC. Selective inhibitors of p38 MAPK (SB203580), JNK (SP600125) and ERK (PD98059) could suppress TNF-alpha-induced CCL2 and ICAM-1 expression, while only p38 MAPK and ERK inhibitors could suppress TNF-alpha-induced VCAM-1 expression. JNK inhibitor was found to up-regulate VCAM-1 expression but did not elicit any additive effect with TNF-alpha on VCAM-1 expression. Moreover, p38 MAPK inhibitor was found to abrogate the TNF-alpha-induced ERK phosphorylation, suggesting that there was a one-way interaction between p38 MAPK and ERK pathways during the TNF-alpha activation. TNF-alpha can play a crucial role in the immunopathogenesis of nephritis by the induction of CCL2, ICAM-1 and VCAM-1 expression via the activation of the intracellular MAPK signaling pathway, which may contribute to macrophage and lymphocyte infiltration.

A comparison of cytokine responses in respiratory syncytial virus and influenza A infections in infants.

Abstract Respiratory syncytial virus (RSV) infection is a major cause of bronchiolitis in infants while influenza A infection usually manifests as upper respiratory tract infection. We hypothesised that the immunological responses of infants to RSV infection and influenza A infection are different. This prospective study was undertaken to compare the cytokine responses during RSV and influenza A infection. Sera and nasopharyngeal aspirates (NPA) were collected from infants with a coryzal illness with or without wheeze who were admitted to the paediatric wards during 1998. Cytokines, adhesion molecules, RANTES, IgE and eosinophil cationic protein (ECP) were measured by enzyme linked immunosorbent assay or fluorescence enzyme immunoassay. The diagnosis of RSV and influenza infections was based on direct immunofluorescence and viral culture. Of the 39 infants studied, RSV infection was confirmed in 11 patients and Influenza A in 10 patients. All RSV patients and one influenza A patient had wheeze during the infection. The serum concentrations of interleukin (IL)-4 and IL-5, regulated upon activation normal T cell expressed and secreted (RANTES) and soluble intercellular adhesion molecule 1 (sICAM-1) in infants with RSV infection were significantly higher than those with influenza A infection (all Pu2009<u20090.02). The concentration of tumour necrosis factor-α (TNF-α) in NPA was significantly lower in infants with RSV infection (Pu2009<u20090.01).nConclusion A predominant T helper cell type 2 cytokine and related immunological response was observed in infants with respiratory syncytial virus infection whereas a predominant pro-inflammatory cytokine response was observed in infants with influenza A infection. This may explain the different clinical manifestations of the two viral infections in infants.

Effects of rosuvastatin on vascular biomarkers and carotid atherosclerosis in lupus: A randomized, double‐blind, placebo‐controlled trial

To study the effect of rosuvastatin on vascular biomarkers and carotid intima‐media thickness (IMT) in systemic lupus erythematosus (SLE).

Interleukin-3, -5, and Granulocyte Macrophage Colony-Stimulating Factor Induce Adhesion and Chemotaxis of Human Eosinophils via p38 Mitogen-Activated Protein Kinase and Nuclear Factor κB

Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-κB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), α6, β2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-κB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases.

Serum concentration of IL-18 correlates with disease extent in young children with atopic dermatitis.

Abstract:u2002 Interleukin (IL)‐18 is a pleiotropic cytokine that plays an important role in both type 1 (Th1) and type 2 (Th2) helper T lymphocyte‐mediated immunity. Previous studies have suggested that IL‐18 may be an inflammatory marker for atopic dermatitis (AD). The purpose of our study was to test whether the serum concentration of IL‐18 is a useful inflammatory marker for assessing AD severity in young children. Nineteen AD patients with a median age of 2.2 years (interquartile range 0.7–4.6 years) were recruited. The severity of AD was clinically determined using the Scoring Atopic Dermatitis (SCORAD) index. Their SCORAD score was 23.9 (range 18.6–34.8). Serum IL‐18 levels were determined by sandwich enzyme immunoassay. The median serum concentration of IL‐18 was 394 pg/ml (interquartile range 204–612 pg/ml). Serum IL‐18 levels correlated with SCORAD scores (r = 0.502, p = 0.029) and their extent component (r = 0.633, p = 0.004). When compared with mild disease with low SCORAD scores, the serum concentration in moderate to severe disease was significantly higher (p = 0.014). We concluded that serum IL‐18 concentration is elevated in young children with AD. It may be a useful inflammatory marker that correlates with the extent component of AD in particular, and differentiates mild disease from more severe disease when used for assessing AD severity in young children.

Anti-Inflammatory and Anti-Allergic Activities of Pentaherb Formula, Moutan Cortex (Danpi) and Gallic Acid

Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL-33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 μg/mL) and GA (10 μg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33-activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-κB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects.

Association between sleep architecture and glucose tolerance in children and adolescents 儿童及青少年的睡眠结构与糖耐量的关系

Short sleep duration is a contributing factor for decreased insulin sensitivity and hyperglycemia. Sleep architecture represents a cyclical pattern of sleep that shifts between sleep Stages N1, N2, N3 (slow wave sleep) and Stage R (rapid eye movement sleep). The aim of the present study was to examine the association between sleep architecture and glucose and insulin metabolism in both normal weight and overweight/obese children and adolescents.

Randomized, double-blind, placebo-controlled trial of herbal therapy for children with asthma.

OBJECTIVESnThe purpose of this trial was to evaluate whether the herbal formula of CUF2 used as complementary therapy improves the clinical symptoms and biochemical markers in children with asthma using inhaled corticosteroids.nnnPATIENTS AND METHODSnIn a double-blind, placebo-controlled prospective trial, 85 children with asthma aged 7-15 years were randomly assigned to receive either a daily oral herbal formula of 0.619-g CUF2 capsule of dried aqueous extract with an equal weight of five herbs (Astragalus mongholius Bunge, Cordyceps sinensis Sacc., Radix stemonae, Bulbus fritillariae cirrhosae, and Radix scutellariae) or placebo for 6 months.nnnRESULTSnThe primary endpoint was the change in steroids dosage; the secondary outcomes included the disease severity score, lung function test, and biochemical markers in blood. Eighty-five (85) children (42 on active treatment and 43 on placebo) completed the 6-month clinical trial. Children randomized to the herbal formula of CUF2 and the placebo showed a similar improvement in clinical symptoms and biomedical markers. The comparison between the CUF2 group and the placebo group showed no significant difference on the dosage of steroids (-2.3 versus -3.1 mg, p = 0.915), disease severity score (-2.3 versus -3.1, p = 0.215), and lung function test of forced expiratory volume in 1 second/forced vital capacity percent (0.1 versus 0.6%, p = 0.809) and peak expiratory flow rate (-7.3 versus -0.6 l/minutes, p = 0.118). No significant difference was found between the two study groups in the biochemical outcomes measured. The intervention effect of CUF2 was smaller than the placebo effect.nnnCONCLUSIONSnThis study provides no evidence to support the use of the herbal formula of CUF2 in children with asthma. Parents are thus advised to discuss with health professionals before choosing an herbal formula in preference to conventional treatment modes.