Regulation of airway epithelial cell NF-κB-dependent gene expression by protein kinase Cδ1

Kristen Page, Jing Li, Limei Zhou, Svetlana Iasvoyskaia, Kevin C. Corbit, Jae Won Soh, I. Bernard Weinstein, Allan R. Brasier, Anning Lin, Marc B. Hershenson

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

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-κB-dependent genes by the novel protein kinase C (PKC) isoform PKCδ in 16HBE14o-human airway epithelial cells, focusing on IL-8 expression. Transient transfection with the constitutively active catalytic subunit of PKCδ (PKCδ-CAT), and treatment with bryostatin 1, an activator of PKCδ, each increased transcription from the IL-8 promoter, whereas overexpression of PKCε had minor effects. Expression of a dominant negative PKCδ mutant (PKCδ-KR) or pretreatment of cells with rottlerin, a chemical PKCδ inhibitor, attenuated TNF-α- and phorbol ester-induced transcription from the IL-8 promoter. Bryostatin 1 treatment increased IL-8 protein abundance in primary airway epithelial cells. Selective activation of PKCδ by bryostatin also activated NF-κB, as evidenced by p65 RelA and p50 NF-κB1 binding to DNA, NF-κB trans-activation, and IκB degradation. The sufficiency of PKCδ to induce NF-κB nuclear translocation and binding to DNA was confirmed in a 16HBE14o-cell line inducibly expressing PKCδ-CAT under the tet-off system. Deletion of the NF-κB response element severely attenuated PKCδ-induced IL-8 promoter activity. Finally, PKCδCAT induced transcription from the GM-CSF, RANTES, and ICAM-1 promoters. Together these data suggest that PKCδ plays a key role in the regulation of airway epithelial cell NF-κB-dependent gene expression.

Original languageEnglish (US)
Pages (from-to)5681-5689
Number of pages9
JournalJournal of Immunology
Volume170
Issue number11
DOIs
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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