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Human Lung Fibroblasts Express Interleukin-6 in Response to Signaling after Mast Cell Contact

Division of Allergy and Clinical Immunology, Department of Internal Medicine, East Tennessee State University, Johnson City, Tennessee

Address correspondence to: Steven Matthew Fitzgerald, East Tennessee State University, Internal Medicine, P.O. Box 70622, Johnson City, TN 37614. E-mail: mattfitzgerald1{at}aol.com

Asthma is a chronic inflammatory disease of the airways. Mast cell–derived cytokines may mediate both airway inflammation and remodeling. It has also been shown that fibroblasts can be the source of proinflammatory cytokines. In the human airways, mast cell–fibroblast interactions may have pivotal effects on modulating inflammation. To study this further, we cocultured normal human lung fibroblasts (NHLF) with a human mast cell line (HMC-1) and assayed for production of interleukin (IL)-6, an important proinflammatory cytokine. When cultured together, NHLF/HMC-1 contact induced IL-6 secretion. Separation of HMC-1 and NHLF cells by a porous membrane inhibited this induction. HMC-1–derived cellular membranes caused an increase in IL-6 production in NHLF. Activation of p38 MAPK was also seen in cocultures by Western blot, whereas IL-6 production in cocultures was significantly inhibited by the p38 inhibitor SB203580. IL-6 production in cocultures was minimally inhibited by a chemical inhibitor of nuclear factor-B (Bay11), indicating that nuclear factor-B may have a minimal role in signaling IL-6 production in mast cell/fibroblasts cocultures. Blockade of inter-cellular adhesion molecule-1, tumor necrosis factor-RI, and surface IL-1ß with neutralizing antibodies failed to significantly decrease IL-6 production in our coculture, indicating that other receptor–ligand associations may be responsible for this activation. These novel studies reveal the importance of cell–cell interactions in the complex milieu of airway inflammation.

Abbreviations: enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • human mast cells-1, HMC-1 • intercellular adhesion molecule, ICAM • interleukin, IL • mitogen-activated protein kinase, MAPK • normal human lung fibroblasts, NHLF • nuclear factor-B, NF-B • phosphate-buffered saline, PBS • phenylmethylsulfonyl fluoride, PMSF • reverse transcriptase–polymerase chain reaction, RT-PCR • tumor necrosis factor, TNF

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