Am. J. Respir. Cell Mol. Biol., Volume 22, Number 6, June, 2000 685-692

Effects of TNF- on Expression of ICAM-1 in Human Airway Epithelial Cells In Vitro
Signaling Pathways Controlling Surface and Gene Expression

Thomas M. Krunkosky, Bernard M. Fischer, Linda D. Martin, Neil Jones, Nancy J. Akley, and Kenneth B. Adler

Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh; and Inspire Pharmaceuticals, Incorporated, Durham, North Carolina

Signaling pathways associated with tumor necrosis factor (TNF)--induced intercellular adhesion molecule 1 (ICAM-1) surface and gene expression were investigated in well differentiated normal human bronchial epithelial (NHBE) cells in air-liquid interface primary culture. Cells were exposed to human recombinant TNF- (hrTNF-; 0.015 to 150 ng/ml [specific activity, 2.86 × 10⁷ U/mg]). TNF- enhanced ICAM-1 surface expression (measured by flow cytometry) and steady-state messenger RNA (mRNA) levels (assessed by Northern hybridization) in concentration- and time-dependent manners. TNF--induced ICAM-1 surface and gene expression were both blocked by the RNA polymerase II inhibitor actinomycin D (0.1 µg/ml), and surface expression was attenuated by a neutralizing monoclonal antibody directed against the TNF- receptor p55 (TNF-RI). The intracellular signaling pathway leading to enhanced expression appeared to involve activation of a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC) because D609, a specific PC-PLC inhibitor, attenuated TNF--induced increases in production of diacyl-glycerol (DAG), a hydrolysis product of PC-PLC, and also attenuated TNF- enhancement of ICAM-1 surface and gene expression. Because DAG formed by action of PC-PLC can activate protein kinase C (PKC), involvement of PKC was investigated. The specific PKC inhibitor calphostin C blocked both surface and gene expression of ICAM-1 in response to TNF- in a concentration-dependent manner. Finally, TNF- stimulated binding of p65 and/or c-rel complexes to the nuclear factor (NF)-B consensus binding site found on the ICAM-1 promoter, and binding of these complexes was inhibited by D609. The results support the following pathway, whereby TNF- enhances expression of ICAM-1 in NHBE cells: TNF-  TNF-RI  PC-PLC  DAG  PKC  (NF-B?)  ICAM-1 mRNA  ICAM-1 surface expression.

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