title: p38 and Src-ERK1/2 pathways regulate crystalline silica-induced chemokine release in pulmonary epithelial cells.
abstract: Crystalline silica has been shown to trigger pulmonary inflammation both in vivo and in vitro, but the underlying molecular mechanisms remain unclear. In the present study we focus on the intracellular signaling pathways regulating chemokine release from lung epithelial cells after crystalline silica exposure. Our results show that silica particles induced a concentration- and time-dependent increase in interleukin (IL)-8 release from the human epithelial lung cell line A549. The IL-8 induction was significantly attenuated by inhibitors of the mitogen-activated protein kinases (MAPKs), p38 (SB202190) and extracellular signal-regulated kinase (ERK)-1 and -2 (PD98059), as well as a general protein tyrosine kinase (PTK) inhibitor (genistein). However, IL-8 induction was most efficiently inhibited by the Src family kinase (SFK) inhibitor, PP2, suggesting a crucial role of SFKs in regulating silica-induced IL-8 release from A549 cells. Silica exposure induced phosphorylation of the MAPKs p38 and ERK1/2, but not JNK or ERK5. Silica also induced a significant phosphorylation of SFKs. Moreover, PP2 inhibited silica-induced phospho-ERK1/2 to near-control levels, whereas phospho-p38 was not significantly reduced by the SFK inhibitor. Our results suggest the presence of two separate signaling pathways which are important in the regulation of silica-induced IL-8 release from A549 cells; one involving SFK-dependent activation of ERK1/2, and the other activation of p38, at least partly independent of SFKs. Experiments with primary type 2 (T2) cells from rat lungs suggest that crystalline silica-induced release of macrophage inflammatory protein (MIP)-2 is regulated through similar mechanisms.
authors.affiliation: Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, N-0403 Oslo, Norway. johan.ovrevik@fhi.no
authors.forename: Johan
authors.initials: J
authors.lastname: Øvrevik
authors.forename: Marit
authors.initials: M
authors.lastname: Låg
authors.forename: Per
authors.initials: P
authors.lastname: Schwarze
authors.forename: Magne
authors.initials: M
authors.lastname: Refsnes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D054426:Chemokine CXCL2; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015846:Monokines / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012822:Silicon Dioxide / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; D015846:Monokines; D011725:Pyridines; D012822:Silicon Dioxide; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one