Am. J. Respir. Cell Mol. Biol., Volume 22, Number 2, February, 2000 235-243

Thrombin Upregulates Interleukin-8 in Lung Fibroblasts via Cleavage of Proteolytically Activated Receptor-I and Protein Kinase C- Activation

Anna Ludwicka-Bradley, Elena Tourkina, Shuzo Suzuki, Elizabeth Tyson, Michael Bonner, John W. Fenton II, Stanley Hoffman, and Richard M. Silver

Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; and State of New York, Department of Health, Wadsworth Center, Albany, New York

Acute and chronic interstitial lung diseases are accompanied by evidence of inflammation and vascular injury. Thrombin activity in bronchoalveolar lavage fluid from such conditions is often increased, as well as interleukin (IL)-8. We observed that conditioned medium from lung fibroblasts exposed to thrombin has chemotactic activity for polymorphonuclear cells, and that this activity can be abolished by antibody to IL-8. We report that thrombin stimulates expression of IL-8 in human lung fibroblasts on both the messenger RNA and protein levels in a time- and dose-dependent manner. Stimulation of IL-8 expression by thrombin is inhibited by specific thrombin inhibitors. Synthetic thrombin receptor agonist peptide-14 mimics thrombin's stimulation of IL-8 expression in a dose-dependent manner consistent with the idea that upregulation of IL-8 by thrombin in human lung fibroblasts requires cleavage of proteolytically activated receptor-I. We demonstrate further that thrombin-induced IL-8 synthesis is regulated by protein kinase (PK) C. PKC- may be involved in the upregulation of lung fibroblast IL-8 by thrombin because stimulation of lung fibroblasts with thrombin caused significant upregulation of PKC- and because PKC- antisense oligonucleotides inhibited the accumulation of PKC- protein and IL-8 protein. Our data suggest that the PKC- isoform increase observed after thrombin stimulation is required for thrombin-induced IL-8 formation by human lung fibroblasts.

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