title: Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway.
abstract: Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3. S100A9 upregulated the release of MCP-1, IL-6, and IL-8 in THP-1 cells. An increase in cytokine was suppressed by CLI-095, a Toll-like receptor (TLR) 4 inhibitor, PP2, a Src inhibitor, rottlerin, a PKCδ inhibitor, MAP kinase inhibitors, including PD98059, SB202190, and SP600125, and BAY-11-7085, an NF-κB inhibitor. Src, PKCδ, ERK1/2, p38 MAPK, and JNK were phosphorylated by S100A9. The phosphorylation of Src and PKCδ was suppressed by CLI-095, and the activation of ERK1/2, p38 MAPK, and JNK was inhibited by CLI-095, PP2, and rottlerin. S100A9 induced NF-κB activity, and the activation was suppressed by CLI-095, PP2, rottlerin, and MAPK kinase inhibitors. In normal and allergic subjects, supernatant from normal and allergic monocytes after stimulation with S100A9 suppressed normal and allergic neutrophil apoptosis, respectively; MCP-1, IL-6, and IL-8 in the supernatant was increased by S100A9. The cytokine secretion induced by S100A9 is related to TLR4, Src, PKCδ, ERK1/2, p38 MAPK, JNK, and NF-κB. Taken together, S100A9 induces anti-apoptotic effect on normal and allergic neutrophils by increasing cytokine secretion of monocytes. These findings may help us to better understand neutrophil apoptosis regulated by S100A9 and pathogenesis of allergic diseases.
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Republic of Korea.
authors.forename: Na Rae
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam 13135, Republic of Korea; Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Republic of Korea.
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Park
authors.affiliation: Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Republic of Korea.
authors.forename: Seong Yeol
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, 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 34824, Republic of Korea.
authors.forename: Da Hye
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Clinical Laboratory Science, Wonkwang Health Science University, Iksan 54538, Republic of Korea. Electronic address: jslee1216@wu.ac.kr.
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Republic of Korea; Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Republic of Korea. Electronic address: orientree@eulji.ac.kr.
authors.forename: In Sik
authors.initials: IS
authors.lastname: Kim
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology; D040502:Calgranulin B / Q000378:metabolism* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: C412373:AG 1879; D000098:Acetophenones; D001578:Benzopyrans; C111835:CCL2 protein, human; D040502:Calgranulin B; D061945:Caspase Inhibitors; D018932:Chemokine CCL2; D003470:Culture Media; D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D011743:Pyrimidines; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; C085746:rottlerin; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3; D053453:Caspase 9
keywords: Allergy; Cytokine; Monocytes; Neutrophil apoptosis; S100A9