Serine protease inhibitors modulate chemotactic cytokine production by human lung fibroblasts in vitro

Chemotactic chemokines can be released from lung fibroblasts in response to interleukin (IL)-1[beta] and tumor necrosis factor (TNF)-[alpha]. An imbalance between proteases and anti-proteases has been observed at inflammatory sites, and, therefore, protease inhibitors might modulate fibroblast release of chemotactic cytokines. To test this hypothesis, serine protease inhibitors (FK-706, [[alpha].sub.1]-antitrypsin, or N[alpha]-p-tosyl-L-lysine chloromethyl ketone) were evaluated for their capacity to attenuate the release of neutrophil chemotactic activity (NCA) or monocyte chemotactic activity (MCA) from human fetal lung fibroblasts (HFL-1). Similarly, the release of the chemoattractants IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor, from HFL-1, were evaluated in response to IL-1[beta] and TNF-[alpha]. NCA, MCA, and chemotactic cytokines were attenuated by FK-706. However, matrix metalloproteinase inhibitors were without effect, and cysteine protease inhibitors only slightly attenuated chemotactic or cytokine release. These data suggest that IL-1[beta] and TNF-[alpha] may stimulate lung fibroblasts to release NCA and MCA by a proteasedependent mechanism and that serine protease inhibitors may attenuate the release. neutrophil; monocyte; interleukin-8; monocyte chemoattractant protein-1; granulocyte/macrophage colony-stimulating factor