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Inhibitory B Kinase 2 Activates Airway Epithelial Cells to Stimulate Bone Marrow Macrophages

Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine; Department of Medicinal Chemistry and Pharmacognosy, University of Illinois; and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois

Correspondence and requests for reprints should be addressed to John W. Christman, M.D., Room 920-N, Clinical Science Building, 840 South Wood Street, Chicago, IL 60612. E-mail: jwc{at}uic.edu

It has not been resolved whether macrophages or airway epithelial cells primarily respond to infectious and inflammatory stimuli and initiate a cell-to-cell inflammatory interaction within the airways. We hypothesized that the airway epithelial cells are primary responders that activate macrophages in response to environmental stimuli. To investigate the unilateral contribution of airway epithelial cells in the activation of macrophages, we developed an in vitro system in which the primary mouse tracheal epithelial cells (MTEC) and primary bone marrow–derived macrophages (BMDM) were incubated together for a brief period of time in a Transwell culture plate. MTEC were transfected with adenoviral vectors that express a constitutively active form of IKK2 (Ad-cIKK2), Ad--Gal, or PBS for 48 h before incubating with the macrophages. Macrophage activation was determined by measuring surface expression of CD11b, activation of NF-B, phagocytic activity and production of reactive oxygen species, and cyclooxygenase (COX)-2 gene expression and production of prostaglandins. Macrophage adherence to epithelial layer was confirmed by CD68 immunostaining and scanning electron microscopy. MTEC cells transfected with Ad-cIKK2 produced increased amounts of IL-6, mouse GRO-, TNF-, and prostaglandin (PG)E₂. Exposure of BMDM to MTEC, transfected with Ad-cIKK2, led to an increase in the CD11b expression and increased adherence of macrophages to the epithelial cell layer. NF-B activation, COX-2 gene expression, and PGD₂ synthesis were also increased in BMDM that were incubated with MTEC transfected with Ad-cIKK2. These data suggest that airway epithelial cells potentially play a primary role in generating inflammatory signals that result in activation of macrophages.

Key Words: airway epithelium • macrophages • lung • inflammation

CLINICAL RELEVANCE Our study helps elucidate the mechanisms related to the initiation and development of inflammation and its progression in the airways and suggests that therapies directed at epithelial cells could modulate macrophage function.