title: Serine protease inhibitors modulate chemotactic cytokine production by human lung fibroblasts in vitro.
abstract: Chemotactic chemokines can be released from lung fibroblasts in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. An imbalance between proteases and antiproteases has been observed at inflammatory sites, and, therefore, protease inhibitors might modulate fibroblast release of chemotactic cytokines. To test this hypothesis, serine protease inhibitors (FK-706, alpha(1)-antitrypsin, or N(alpha)-p-tosyl-L-lysine chloromethyl ketone) were evaluated for their capacity to attenuate the release of neutrophil chemotactic activity (NCA) or monocyte chemotactic activity (MCA) from human fetal lung fibroblasts (HFL-1). Similarly, the release of the chemoattractants IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor, from HFL-1, were evaluated in response to IL-1beta and TNF-alpha. NCA, MCA, and chemotactic cytokines were attenuated by FK-706. However, matrix metalloproteinase inhibitors were without effect, and cysteine protease inhibitors only slightly attenuated chemotactic or cytokine release. These data suggest that IL-1beta and TNF-alpha may stimulate lung fibroblasts to release NCA and MCA by a protease-dependent mechanism and that serine protease inhibitors may attenuate the release.
authors.affiliation: Research Service, Southern Arizona Veterans Health Care System, and Arizona Respiratory Center, University of Arizona, Tucson, Arizona 85723, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Numanami
authors.forename: Sekiya
authors.initials: S
authors.lastname: Koyama
authors.forename: Esturo
authors.initials: E
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haniuda
authors.forename: Dan K
authors.initials: DK
authors.lastname: Nelson
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hoyt
authors.forename: Jon L
authors.initials: JL
authors.lastname: Freels
authors.forename: Michael P
authors.initials: MP
authors.lastname: Habib
authors.forename: Richard A
authors.initials: RA
authors.lastname: Robbins
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D010196:Pancreatic Elastase / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D018932:Chemokine CCL2; C109799:FK 706; D007375:Interleukin-1; D016209:Interleukin-8; D011759:Pyrrolidines; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D014107:Tosyllysine Chloromethyl Ketone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010196:Pancreatic Elastase