| First Author | Wyatt TA | Year | 2014 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 307 |
| Issue | 8 | Pages | L643-51 |
| PubMed ID | 25150062 | Mgi Jnum | J:222063 |
| Mgi Id | MGI:5643909 | Doi | 10.1152/ajplung.00373.2013 |
| Citation | Wyatt TA, et al. (2014) cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 307(8):L643-51 |
| abstractText | Lung injury caused by inhalation of dust from swine-concentrated animal-feeding operations (CAFO) involves the release of inflammatory cytokine interleukin 8 (IL-8), which is mediated by protein kinase C-epsilon (PKC-epsilon) in airway epithelial cells. Once activated by CAFO dust, PKC-epsilon is responsible for slowing cilia beating and reducing cell migration for wound repair. Conversely, the cAMP-dependent protein kinase (PKA) stimulates contrasting effects, such as increased cilia beating and an acceleration of cell migration for wound repair. We hypothesized that a bidirectional mechanism involving PKA and PKC regulates epithelial airway inflammatory responses. To test this hypothesis, primary human bronchial epithelial cells and BEAS-2B cells were treated with hog dust extract (HDE) in the presence or absence of cAMP. PKC-epsilon activity was significantly reduced in cells that were pretreated for 1 h with 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) before exposure to HDE (P < 0.05). HDE-induced IL-6, and IL-8 release was significantly lower in cells that were pretreated with 8-Br-cAMP (P < 0.05). To exclude exchange protein activated by cAMP (EPAC) involvement, cells were pretreated with either 8-Br-cAMP or 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-CPT-2Me-cAMP) (EPAC agonist). 8-CPT-2Me-cAMP did not activate PKA and did not reduce HDE-stimulated IL-6 release. In contrast, 8-Br-cAMP decreased HDE-stimulated tumor necrosis factor (TNF)-alpha-converting enzyme (TACE; ADAM-17) activity and subsequent TNF-alpha release (P < 0.001). 8-Br-cAMP also blocked HDE-stimulated IL-6 and keratinocyte-derived chemokine release in precision-cut mouse lung slices (P < 0.05). These data show bidirectional regulation of PKC-epsilon via a PKA-mediated inhibition of TACE activity resulting in reduced PKC-epsilon-mediated release of IL-6 and IL-8. |
