title: Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis.
abstract: We have previously shown that tumor necrosis factor (TNF)α produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b+TLR4+ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4+ Clara cells could be derived from bone marrow. SAA3-induced TNFα expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNFα in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.forename: Y
authors.initials: Y
authors.lastname: Sakurai
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Y
authors.initials: Y
authors.lastname: Maru
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018845:CD11 Antigens / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000556:secondary*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004731:Endotoxins / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D011014:Pneumonia / Q000473:pathology*; D000685:Serum Amyloid A Protein / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018845:CD11 Antigens; D040501:Calgranulin A; D004731:Endotoxins; D009281:Naphthalenes; C086145:S100a8 protein, mouse; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C031721:naphthalene