Mechanisms in fluoride-induced interleukin-8 synthesis in human lung epithelial cells

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 pathw ays downstream of the G proteins have been examined. NaF induced a weak, bu t sustained increase in PKC activity. In contrast, the PKC activator TPA in duced a relatively strong, but transient effect and augmented the NaF-induc ed PKC activity. TPA induced a marked IL-8 response compared to NaF. PDB, a nother PKC activator, was less effective, but augmented the IL-8 response t o 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 preven ted the NaF-induced IL-8 response. Inhibition of the MAP kinase p38 by SB20 2190 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 res ponse was weakly augmented by the PKA stimulator forskolin and the G(i) inh ibitor pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-indu ced IL-8 response, but the measured effect was not statistically significan t. BAPTA-AM, KN93 and W7, that inhibit Ca2 + -linked effects, did not affec t the IL-8 response. Furthermore, the tyrosine kinase inhibitor genestein, the PI-3 kinase inhibitor wortmannin and phosphatase inhibition were withou t 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-depen dent pathway counteracted the response. Tyrosine kinases, Ca2 (+) -linked p athways, PI-3 kinase, PKA and phosphatase inhibition seem to play no or min or roles in the fluoride-induced IL-8 response. (C) 2001 Elsevier Science I reland Ltd. All rights reserved.