title: House Dust Mite Allergen Regulates Constitutive Apoptosis of Normal and Asthmatic Neutrophils via Toll-Like Receptor 4.
abstract: House dust mites (HDMs) induce allergic diseases such as asthma. Neutrophil apoptosis is an important process of innate immunity, and its dysregulation is associated with asthma. In this study, we examined the effects of HDM on constitutive apoptosis of normal and asthmatic neutrophils. Extract of Dermatophagoides pteronissinus (DP) inhibited neutrophil apoptosis, but Dermatophagoides farinae extract had no effect. Anti-apoptotic signaling mediated by DP involves in TLR4, Lyn, PI3K, Akt, ERK, and NF-κB in normal neutrophils. DP delayed cleavage of procaspase 9 and procaspase 3 and the decrease in Mcl-1 expression. Supernatant collected from DP-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils, and S100A8 and S100A9 were identified as anti-apoptotic proteins in the supernatant. S100A8 and S100A9 transduced the anti-apoptotic signal via TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. DP also suppressed asthmatic neutrophil apoptosis and induced secretion of S100A8 and S100A9, which delayed the constitutive apoptosis. The anti-apoptotic effects of DP, S100A8 and S100A9 in asthmatic neutrophils are associated with TLR4, Lyn, PI3K, Akt, ERK, and NF-κB. The concentrations of S100A8 and S100A9 were significantly elevated in asthmatic bronchoalveolar lavage fluid (BALF) when compared to normal BALF (p<0.01), but not in serum. S100A8 concentration in BALF was positively correlated with the number of BALF neutrophils and negatively correlated with FEV1(%). These findings improve our understanding of the role of HDM in regulation of neutrophil apoptosis in normal individuals and asthmatics and will enable elucidation of asthma pathogenesis.
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 301-768, Republic of Korea.
authors.forename: Do Hyung
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Respiratory Internal Medicine, College of Medicine, Konyang University, Daejeon, 302-718, Republic of Korea.
authors.forename: Eugene
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Clinical Laboratory Science, Wonkwang Health Science University, Iksan, 570-750, Republic of Korea.
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 301-768, Republic of Korea.
authors.forename: Na Rae
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Senior Healthcare, BK21 plus program, Graduate School, Eulji University, Daejeon 301-746, Republic of Korea.
authors.forename: Seung Yeop
authors.initials: SY
authors.lastname: Baek
authors.affiliation: Department of Senior Healthcare, BK21 plus program, Graduate School, Eulji University, Daejeon 301-746, Republic of Korea.
authors.forename: Ayoung
authors.initials: A
authors.lastname: Gu
authors.affiliation: Department of Senior Healthcare, BK21 plus program, Graduate School, Eulji University, Daejeon 301-746, Republic of Korea.
authors.forename: Da Hye
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 301-768, Republic of Korea; Department of Senior Healthcare, BK21 plus program, Graduate School, Eulji University, Daejeon 301-746, Republic of Korea.
authors.forename: In Sik
authors.initials: IS
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology; D040502:Calgranulin B / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002457:Cell Extracts / Q000494:pharmacology*; D040001:Dermatophagoides farinae / Q000737:chemistry / Q000276:immunology*; D040002:Dermatophagoides pteronyssinus / Q000737:chemistry / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D000485:Allergens; D040501:Calgranulin A; D040502:Calgranulin B; D002457:Cell Extracts; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3