title: Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells.
abstract: Sodium fluoride (NaF) has previously been reported to induce a strong IL-8 response in human epithelial lung cells (A549) via mechanisms that seem to involve the activation of G proteins. In the present study the signal pathways downstream of the G proteins have been examined. NaF induced a weak, but sustained increase in PKC activity. In contrast, the PKC activator TPA induced a relatively strong, but transient effect and augmented the NaF-induced PKC activity. TPA induced a marked IL-8 response compared to NaF. PDB, another PKC activator, was less effective, but augmented the IL-8 response to NaF. Pretreatment with TPA for 20 h, or the PKC inhibitor GF109203X for 1 h, abolished the basal and NaF-induced PKC activities and partially prevented the NaF-induced IL-8 response. Inhibition of the MAP kinase p38 by SB202190 partially reduced the IL-8 response to NaF, whereas a reduction in ERK activity by PD98059 led to an increased response. The NaF-induced IL-8 response was weakly augmented by the PKA stimulator forskolin and the G(i) inhibitor pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-induced IL-8 response, but the measured effect was not statistically significant. BAPTA-AM, KN93 and W7, that inhibit Ca(2+)-linked effects, did not affect the IL-8 response. Furthermore, the tyrosine kinase inhibitor genestein, the PI-3 kinase inhibitor wortmannin and phosphatase inhibition were without effects. In conclusion, the data suggest that NaF-induced increase of IL-8 in A549 cells involved PKC- and p38-linked pathways, whereas an ERK-dependent pathway counteracted the response. Tyrosine kinases, Ca(2+)-linked pathways, PI-3 kinase, PKA and phosphatase inhibition seem to play no or minor roles in the fluoride-induced IL-8 response.
authors.affiliation: Department of Environmental Medicine, National Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. magne.refnes@folkhelsa.no
authors.forename: M
authors.initials: M
authors.lastname: Refsnes
authors.forename: E V
authors.initials: EV
authors.lastname: Thrane
authors.forename: M
authors.initials: M
authors.lastname: Låg
authors.forename: G H
authors.initials: GH
authors.lastname: Thoresen
authors.forename: P E
authors.initials: PE
authors.lastname: Schwarze
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D007546:Isoquinolines / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D012969:Sodium Fluoride / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin; D000096926:Benzenesulfonamides
chemical_list: D000730:Androstadienes; D001596:Benzylamines; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D004533:Egtazic Acid; D005419:Flavonoids; D019833:Genistein; D007211:Indoles; D016209:Interleukin-8; D007546:Isoquinolines; D008301:Maleimides; D019319:Okadaic Acid; D037342:Pertussis Toxin; D011493:Protein Kinase C; D012969:Sodium Fluoride; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate; D014638:Vanadates; D010566:Virulence Factors, Bordetella; D000077191:Wortmannin; C072105:KN 93; D000096926:Benzenesulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C017967:W 7; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one