Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)-induced epithelial cytokine release through aryl hydrocarbon receptor in asthma.

BACKGROUND: Environmental pollutants, which coexist with allergens, have been associated with the exacerbation of asthma. However, the underlying molecular mechanisms remain elusive. We sought to determine whether benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced asthma and its underlying mechanisms. METHODS: The effect of BaP was investigated in Der f 1-induced mouse model of asthma, including airway hyper-responsiveness, allergic inflammation, and epithelial-derived cytokines. The impact of BaP on Der f 1-induced airway epithelial cell oxidative stress (ROS) and cytokine release was further analyzed. The role of aryl hydrocarbon receptor (AhR) signaling in BaP-promoted Der f 1-induced ROS, cytokine production, and allergic inflammation was also investigated. RESULTS: Compared with Der f 1, BaP co-exposure with Der f 1 led to airway hyper-responsiveness and increased lung inflammation in mouse model of asthma. Increased expression of TSLP, IL-33, and IL-25 was also found in the airways of these mice. Moreover, BaP co-exposure with Der f 1 activated AhR signaling with increased expression of AhR and CYP1A1 and promoted airway epithelial ROS generation and TSLP and IL-33, but not IL-25, expression. Interestingly, AhR antagonist CH223191 or cells with AhR knockdown abrogated the increased expression of ROS, TSLP, and IL-33. Furthermore, ROS inhibitor N-acetyl-L-cysteine (NAC) also suppressed BaP co-exposure-induced expression of epithelial TSLP, IL-33, and IL-25. Finally, AhR antagonist CH223191 and NAC inhibited BaP co-exposure with Der f 1-induced lung inflammation. CONCLUSIONS: Our findings suggest that BaP facilitates Der f 1-induced epithelial cytokine release through the AhR-ROS axis.

Functional interaction of cockroach allergens and mannose receptor (CD206) in human circulating fibrocytes.

BACKGROUND: The innate pattern recognition C-type-lectin receptors (CLRs), including mannose receptor (MRC1; CD206), have been suggested to functionally interact with allergens and are critical in controlling immune response. Fibrocytes have been considered to play a role in allergic asthma. Here we sought to investigate the functional interaction of cockroach allergens with CD206 in fibrocytes. METHODS: Profiling of N-linked glycans from natural purified cockroach allergen Bla g 2 was accomplished by MALDI-MS. The binding activity of cockroach allergens to CD206 was determined by solid-phase binding assays. Levels of CD206 expression on human fibrocytes and CD206 mediated signaling and cytokine production in Bla g 2 treated fibrocytes were determined. RESULTS: Profiling of N-linked glycans from Bla g 2 revealed a predominance of small, mannose-terminated glycans with and without fucose. Significant binding of Bla g 2 to CD206 was observed, which was inhibited by yeast mannan (a known CD206 ligand), free mannose, and a blocking antibody (anti-hMR). Flow cytometric analyses of human fibrocytes (CD45(+) and collagen-1(+)) showed selective expression of CD206 on fibrocytes. Functionally, a concentration-dependent uptake of FITC labeled Bla g 2 by fibrocytes was observed, but was significantly inhibited by anti-hMR. Bla g 2 can stimulate up-regulation of inflammatory cytokines including TNF-alpha and IL-6 and activation of nuclear factor kappa B (NF-kB/p65), p38 mitogen-activated protein kinase (p38), ERK, and JNK in cultured fibrocytes. This increased secretion of TNF-alpha and IL-6 and activation of NF-kB, ERK, and JNK was significantly inhibited by the addition of either mannan or mannose. Furthermore, Bla g 2 induced increase in TNF-alpha and IL-6 production was also inhibited by the use of NF-kB, ERK, and JNK inhibitors. CONCLUSION: These results provide evidence supporting the existence of a functional cockroach allergen-CD206 axis in human fibrocytes, suggesting a role for CD206 in regulating allergen induced allergic responses in asthma.

Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease associated with the local infiltration of T helper type 2 (Th2) cells. The ST2 gene encodes both membrane-bound ST2L and soluble ST2 (sST2) proteins by alternative splicing. The orphan receptor ST2L is functionally indispensable for Th2 cells. We found a significant genetic association between AD and the -26999G/A single nucleotide polymorphism (SNP) (chi2-test, raw P-value=0.000007, odds ratio 1.86) in the distal promoter region of the ST2 gene (chromosome 2q12) in a study of 452 AD patients and 636 healthy controls. The -26999A allele common among AD patients positively regulates the transcriptional activity of the ST2 gene. In addition, having at least one -26999A allele correlated with high sST2 concentrations and high total IgE levels in the sera from AD patients. Thus, the -26999A allele is correlated with an increased risk for AD. We also found that the -26999G/A SNP predominantly affected the transcriptional activity of hematopoietic cells. Immunohistochemical staining of a skin biopsy specimen from an AD patient in the acute stage showed ST2 staining in the keratinocytes as well as in the infiltrating cells in the dermal layer. Our data show that functional SNPs in the ST2 distal promoter region regulate ST2 expression which induces preferential activation of the Th2 response. Our findings will contribute to the evaluation of one of the genetic risk factors for AD.