title: Methotrexate stimulates lung epithelial cells to release inflammatory cell chemotactic activities.
abstract: Methotrexate-induced pneumonitis has been reported as an infrequent but potentially serious complication of therapy in a variety of malignant and benign conditions. Because inflammatory cell infiltration is concerned with the development of methotrexate-induced pneumoinitis, and because airway epithelial cells participate in the orchestration of lung inflammation, the authors determined whether methotrexate might stimulate airway epithelial cells (A549 cells) to release neutrophil, monocyte, and eosinophil chemotactic activities (NCA, MCA, and ECA). A549 cells released NCA, MCA, and ECA in a dose- and time-dependent manner in response to methotrexate. Partial characterization revealed the heterogeneity of NCA, MCA, and ECA. The release of chemotactic activity was blocked by lipoxygenase inhibitors and cycloheximide. NCA was inhibited by leukotriene (LT) B(4) receptor antagonist, and anti-interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) antibodies. MCA was attenuated by LTB(4) receptor antagonist, and anti-monocyte chemoattractant protein (MCP)-1 and granulocyte-macrophage CSF (GM-CSF) antibodies. ECA was attenuated by LTB(4) receptor antagonist, and anti-IL-8 and GM-CSF antibodies. The release of IL-8, G-CSF, MCP-1, GM-CSF, and LTB(4) from A549 cells significantly increased in response to methotrexate. The mRNA expression of IL-8 and MCP-1 was augmented by methotrexate stimulation. These data suggest that type II epithelial cells may modulate inflammatory cell recruitment into the lung by releasing NCA, MCA, and ECA in response to methotrexate.
authors.affiliation: The National Chuushin Matsumoto Hospital, Matsumoto, Japan. yskoyama@go.tvm.ne.jp
authors.forename: Sekiya
authors.initials: S
authors.lastname: Koyama
authors.forename: Etsuro
authors.initials: E
authors.lastname: Sato
authors.forename: Akemi
authors.initials: A
authors.lastname: Takamizawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsukadaira
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haniuda
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Numanami
authors.forename: Sonoko
authors.initials: S
authors.lastname: Nagai
authors.forename: Takateru
authors.initials: T
authors.lastname: Izumi
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D019138:Antibodies, Blocking; D000964:Antimetabolites, Antineoplastic; D018925:Chemokines; D004791:Enzyme Inhibitors; D008727:Methotrexate