Regulation of airway epithelial cell NF-kappa B-dependent gene expression by protein kinase C delta.

Airway epithelial cells synthesize proinflammatory molecules such as IL-8, GM-CSF, RANTES, and ICAM-1, the expression of which is increased in the airways of patients with asthma. We investigated the regulation of these NF-kappa B-dependent genes by the novel protein kinase C (PKC) isoform PKC delta in 16HBE14o- human airway epithelial cells, focusing on IL-8 expression. Transient transfection with the constitutively active catalytic subunit of PKC delta (PKC delta-CAT), and treatment with bryostatin 1, an activator of PKC delta, each increased transcription from the IL-8 promoter, whereas overexpression of PKC epsilon had minor effects.

Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells.

In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-8 expression depends on the activation of two distinct signaling pathways, one constituted in part by activator protein (AP)-1 and the other by nuclear factor (NF)-kappaB. We examined the upstream signaling intermediates responsible for IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in this system, hypothesizing that p21 Ras and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase (MEKK)-1 function as common upstream activators of both the AP-1 and NF-kappaB pathways. TNF-alpha treatment induced both Ras and MEKK1 activation.

Regulation of human airway epithelial cell IL-8 expression by MAP kinases.

Recent studies indicate that maximal IL-8 protein expression requires activation of NF-kappaB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-kappaB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-kappaB, ERK, JNK, and p38 for TNF-alpha-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line.