Yu-Te Chu

Extreme BMI predicts higher asthma prevalence and is associated with lung function impairment in school-aged children†

The prevalence of obesity and asthma has increased in recent decades. We investigated the relationship between body mass index (BMI) and lung function, and also tried to determine if asthma prevalence differs between obese and non‐obese children.

Effects of vitamin D3 on expression of tumor necrosis factor-α and chemokines by monocytes.

The association between vitamin D deficiency and asthma epidemic has been recognized. Tumor necrosis factor (TNF)-alpha and chemokines play important roles in pathogenesis of asthma. However, whether vitamin D has immunoregulatory function on TNF-alpha and chemokines expression in human monocytes is still unknown. The human monocytic cell line, THP-1 cells and human primary monocytes were pretreated with various concentration of 1alpha,25-(OH)(2)D(3) for 2 h before stimulation with lipopolysaccharide (LPS). Supernatants were collected 24 or 48 h after LPS stimulation. The levels of TNF-alpha, interferon-inducible protein 10 (IP-10)/CXCL10 (the Th1-related chemokine), macrophage-derived chemokine (MDC)/ CCL22 (the Th2-related chemokine), and interleukin 8 (IL-8)/CXCL8 (the neutrophil chemoattractant) were measured by ELISA. 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and IP-10 expression in LPS-stimulated THP-1 and human primary monocytes. However, 1alpha,25-(OH)(2)D(3), especially in higher concentration, could significantly enhance MDC expression. 1alpha,25-(OH)(2)D(3) had no significant effects on IL-8 expression. We found 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and Th1-related chemokine IP-10, which both play important roles in pathogenesis of severe refractory asthma and autoimmune diseases. However, 1alpha,25-(OH)(2)D(3) enhanced Th2-related chemokine MDC, which may result in Th2 inflammatory cell recruitment and thus adversely affect asthmatic patients. Although vitamin D has potential utility in the treatment of asthma and autoimmune diseases, excessive use of vitamin D may not be suitable in patients with Th2 allergic diseases.

Effect of the Chinese Herb Extract Osthol on IL-4-induced Eotaxin Expression in BEAS-2B Cells

BACKGROUND Asthma is an allergic inflammatory disease of the airways. The interaction between bronchial epithelial cells and eosinophils is an important feature of an asthma attack. Eotaxin, an eosinophil-specific C-C chemokine, is a potent chemoattractant involved in the mobilization of eosinophils into the airway after allergic stimulation. Cnidii monnieri fructus, the dried fruit of Cnidium monnieri Cusson, has been used as an antipruritogenic agent in ancient China. OsthoL is the major component of Cnidii monnieri fructus extract. We investigated the ability of osthol to regulate cytokine-induced eotaxin expression in the human bronchial epithelial cell line BEAS-2B. METHODS BEAS-2B cells were pretreated with osthol at different concentrations (0.1-10 microM), and then stimulated with interleukin (IL)-4 alone, or in combination with tumor necrosis factor (TNF)-alpha. Eotaxin levels were determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. STAT6 (signal transducer and activator of transcription 6) and MAPK (mitogen-activated protein kinase) expressions were evaluated by Western blotting, to detect possible intracellular signal transduction. RESULTS IL-4 and TNF-alpha significantly induced eotaxin expression in BEAS-2B cells. Expression of eotaxin was suppressed by osthol (0.1-10 microM) in a dose-dependent manner. Osthol did not suppress IL-4-induced p38, ERK or JNK expression. Osthol did suppress IL-4-induced STAT6 in a dose-dependent manner. CONCLUSION Osthol suppressed IL-4-induced eotaxin in BEAS-2B cells via inhibition of STAT6 expression. This data suggest that osthol might have potential for treating allergic airway inflammation.

Effects of All-Trans Retinoic Acid on Th1- and Th2-Related Chemokines Production in Monocytes

Low vitamin C and reduced alpha-carotene intake are associated with increased asthma risk in children. In addition, mean serum vitamin A concentrations are significantly lower in asthmatic children than in controls. All-trans retinoic acid (ATRA) is a derivative of vitamin A. Macrophage-derived chemokine (MDC) is a T helper cell-type 2 (Th2)-related chemokine involved in the recruitment of Th2 cells toward inflammatory sites. On the other hand, Th1-related chemokine, interferon-inducible protein 10 (IP-10)/CXCL10 is also important in allergic inflammation. Both Th1- and Th2-related chemokines play an important role in allergic asthma. To survey whether ATRA and ascorbic acid effect Th1- and Th2-related chemokine expression in monocytes. To test this, THP-1 cells were pre-treated with ATRA or ascorbic acid and stimulated by lipopolysaccharide (LPS) or poly I:C. Supernatants were measured for Th2-related (MDC) and Th1-related (IP-10) chemokine concentrations by ELISA. The effects of ATRA on mitogen-activated protein kinase (MAPK) and NFkb were evaluated with Western blotting. After stimulation, ATRA significantly down-regulated MDC and IP-10 in a dose-dependent manner. Similarly, ascorbic acid reduced the LPS-induced changes in MDC but only with a high dose. However, asorbic acid had no effect on IP-10 changes either induced by LPS or poly I:C. RT-PCR showed ATRA inhibited IP-10 expression through decreasing the level of transcription. Furthermore, ATRA suppressed the expression of LPS-stimulated c-Raf, MKK1/2 and ERK expression of THP-1 cells. In conclusion, ATRA suppressed Th2- and Th1-related chemokines expression in THP-1 cells, at least in part via the c-Raf-MKK1/2-ERK/MAPK pathway.

Probiotics and allergy in children – An update review

Pan S‐J, Kuo C‐H, Lam K‐P, Chu Y‐T, Wang W‐L, Hung C‐H. Probiotics and allergy in children – An update review.
Pediatr Allergy Immunol 2010: 21: e659–e666.
© 2010 John Wiley & Sons A/S

Effects of formoterol and salmeterol on the production of Th1- and Th2-related chemokines by monocytes and bronchial epithelial cells

It is unknown whether formoterol and salmeterol, two long-acting β2-adrenoreceptor agonists, have regulatory functions in the production of T-helper cell (Th) type 2- and Th1-related chemokines by monocytes and bronchial epithelial cells. In the present study, the effects of formoterol and salmeterol on lipopolysaccharide (LPS)-induced expression of the Th2-related chemokine macrophage-derived chemokine (MDC; CCL22) and the Th1-related chemokine interferon-γ-inducible protein (IP)-10 (CXCL10) were investigated in a monocytic cell line, THP-1, and in human primary monocytes. In addition, their effects on the expression of the Th2-related chemokine thymus- and activation-regulated chemokine (TARC; CCL17) were evaluated in an epithelial cell line, BEAS-2B. Formoterol enhanced MDC but suppressed IP-10 production in monocytes induced by LPS. Higher doses of salmeterol were required to enhance LPS-induced MDC expression in THP-1 cells. Formoterol and salmeterol could significantly suppress TARC expression in BEAS-2B cells. These effects could be reversed by a selective β2-adrenoreceptor antagonist, ICI-118551. Formoterol- and LPS-induced MDC expression was inhibited by budesonide. Both long-acting β2-adrenoreceptor agonists suppressed thymus- and activation-regulated chemokine expression in bronchial epithelial cells mediated via β2-adrenoreceptors. Formoterol at physiological concentrations could suppress lipopolysaccharide-induced T-helper cell type 1-related chemokine (interferon-γ-inducible protein-10) but enhance T-helper cell type 2-related chemokine (macrophage-derived chemokine) expression in human monocytes. Long-acting β2-adrenoreceptor agonists may increase T-helper cell type 2-related chemokine expression in monocytes and T-helper cell type 2 recruitment and, therefore, long-acting β2-adrenoreceptor agonist monotherapy may not be an appropriate therapeutic option for asthma.

Regulation of cytokine expression in human plasmacytoid dendritic cells by prostaglandin I2 analogues.

Plasmacytoid dendritic cells (pDCs) are critical in controlling adaptive immunity, but the mechanisms governing cytokine expression remain incompletely defined. Analogues of prostaglandin (PG)I2, such as iloprost, can modulate functions of myeloid dendritic cells, but their involvement in the regulation of human pDCs remains unknown. To this end, the regulatory role of PGI2 analogues on cytokine expression in pDCs was investigated. Circulating pDCs were magnetically sorted with BDCA-4 cell isolation kits from human peripheral blood mononuclear cells and treated with varying concentrations of iloprost with or without the addition of Toll-like receptor agonists, or an I prostanoid (IP) receptor antagonist, CAY10449. The levels of tumour necrosis factor (TNF)-α, interferon (IFN)-α and interleukin (IL)-10 were measured by ELISA. Iloprost induced IL-10 expression, but suppressed CpG oligodeoxynucleotide- (or imiquimod-) induced TNF-α and IFN-α production in pDCs. This effect was reversed by the addition of CAY10449. Forskolin, a cyclic adenosine monophosphate activator, conferred a similar modulating effect to that noted in iloprost-treated pDCs, although a higher concentration of forskolin was required to exert the same effect. Iloprost enhanced interleukin-10 and suppressed Toll-like receptor-mediated tumour necrosis factor-α and interferon-α production of human plasmacytoid dendritic cells via the I prostanoid receptor and, in part, the cyclic adenosine monophosphate pathway.

The Natural Flavonoid Apigenin Suppresses Th1- and Th2-Related Chemokine Production by Human Monocyte THP-1 Cells Through Mitogen-Activated Protein Kinase Pathways

Dietary flavonoids have various biological functions, and there is increasing evidence that reduced prevalence and severity of allergic reactions are associated with the intake of flavonoids. Among natural flavonoids, apigenin is a potent anti-inflammatory agent. However, the mechanisms of apigenins effect remain uncertain. Monocyte-derived chemokine (MDC) plays a pivotal role in recruiting T-helper (Th) 2 cells in the allergic inflammation process. In the late phase of allergic inflammation, the Th1 chemokine interferon-inducible protein 10 (IP-10) has also been found in elevated levels in the bronchial alveolar fluid of asthmatic children. We used human THP-1 monocyte cells, pretreated with or without apigenin, prior to lipopolysaccharide stimulation. By means of enzyme-linked immunosorbent assay, we found that apigenin inhibited production of both MDC and IP-10 by THP-1 cells and that the suppressive effect of apigenin was not reversed by the estrogen receptor antagonist ICI182780. The p65 phosphorylation of nuclear factor kappaB remained unaffected, but the phosphorylation of p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase mitogen-activated protein kinase pathways were all blocked. We found that inhibition of c-raf phosphorylation might be the target of apigenins anti-inflammation property.

Natural flavone kaempferol suppresses chemokines expression in human monocyte THP-1 cells through MAPK pathways.

There is increasing evidence that daily intake of flavonoids reduced severity and prevalence of allergic diseases. However, the mechanism of its antiinflammatory effects in allergic diseases remains uncertain. Kaempferol, which belongs to the flavone group, is a strong antioxidant among natural flavonoids and is the essential component of many beverages and vegetables. Because chemokine is one of the key mediators in allergic inflammatory process, we investigated the effect of kaempferol on chemokines expression in monocytes. Our data demonstrated that kaempferol significantly inhibited the lipopolysaccharide (LPS)-induced production of monocyte-derived chemokine (MDC), interferon gamma-induced protein 10 (IP-10), and interleukin-8 (IL-8) in THP-1 cells. Growth-related oncogene-α (GRO-α) was also suppressed at a higher concentration. We also found that kaempferol was able to suppress LPS-induced mitogen-activated protein kinase (MAPK) pathways, as well as the phosphorylation of upstream c-raf and MEK1/2. In brief, kaempferol suppressed LPS-induced T helper 1 (Th1), T helper 2 (Th2), and neutrophil-related chemokines production in monocytes might be via the MAPK pathways.

Sublingual Immunotherapy in Children: An Updated Review

Although pharmacological therapy and allergen avoidance are effective means of managing allergic disease, allergen-specific immunotherapy is able to treat not only the symptoms, but also the underlying causes of the disease. Sublingual immunotherapy (SLIT) has been shown to be effective in patients with allergic diseases. It has demonstrated long-term clinical benefits and shown the potential to modify the course of allergic disease in children with rhinitis, conjunctivitis, and asthma. The precise mechanisms of SLIT remain unclear, but antigen-presenting cells in the oral mucosa may induce regulatory T-cells that suppress the allergic immune response by increasing production of interleukin-10. SLIT has also been shown to increase allergen-specific IgG antibodies that antagonize and block the allergic response. SLIT was well tolerated in all reported, double-blinded, placebo-controlled, randomized trials. SLIT is an ideal means of treating the pediatric population because of its excellent safety and good compliance. However, the optimal dose and duration of SLIT require further investigation.