Am. J. Respir. Cell Mol. Biol., Volume 22, Number 5, May, 2000 628-634

Different Expression of TNF- Receptors and Prostaglandin E₂ Production in Normal and Fibrotic Lung Fibroblasts
Potential Implications for the Evolution of the Inflammatory Process

Carlo Vancheri, Maria Angela Sortino, Valerio Tomaselli, Claudio Mastruzzo, Fabrizio Condorelli, Guglielmo Bellistrí, Maria P. Pistorio, Pier Luigi Canonico, and Nunzio Crimi

Institute of Respiratory Diseases and Institute of Pharmacology, University of Catania, Catania; and Department of Internal Medicine, University of Pavia, Pavia, Italy

Normal human lung fibroblasts downregulate the production of tumor necrosis factor (TNF)- by activated monocytes through the production of prostaglandin E₂ (PGE₂), contributing to the local control of the inflammatory process. In this study, we provide evidence that fibroblasts derived from diseased tissue, such as fibrotic lung fibroblasts, exhibit different functional features compared with normal cells, with particular regard to their modulatory role. Indeed, fibrotic fibroblasts (FF) spontaneously produced less PGE₂ (3,300 ± 410 pg/ml) compared with normal fibroblasts (NF) (7,500 ± 270 pg/ml) and, as a consequence, they showed a reduced ability to downregulate the production of TNF- by lipopolysaccharide (LPS)- activated monocytes. The percentage of inhibition induced by normal cells on the production of TNF- by LPS-activated monocytes was 61 ± 5.9%, whereas the inhibitory effect exerted by fibrotic cells was reduced to 32 ± 4% (P < 0.01). We have also observed that the ability of TNF- to induce PGE₂ was impaired in FF and was related to a reduced expression of cyclooxygenase 2. This was possibly due to the reduction of the expression of TNF receptors (TNFRs) in fibrotic cell lines compared with normal cell lines. Flow cytometry revealed that the mean fluorescence intensity (MFI) of both isoforms of TNFR was significantly lower in FF compared with NF. The MFI of TNFR1 was 3.55 ± 0.12 for NF and 1.78 ± 0.35 for FF (P < 0.001). The MFI of TNFR2 was 1.95 ± 0.27 for NF and 0.99 ± 0.16 for FF (P < 0.01). The analysis of the effect of TNF- on some functions associated with collagen metabolism in NF and FF showed an increase of the expression of the receptor for collagen type I (₂₁ integrin) in NF (42 ± 10%) and an even larger increase in FF (102 ± 23%) (P < 0.05). Interestingly, unlike NF, TNF- failed to increase matrix metalloproteinase 1 levels in FF and did not cause any growth inhibition in these cells. The reduced capability of fibrotic cells to produce PGE₂ either spontaneously or after TNF- treatment may lead to an unrestrained release of TNF- from activated monocytes and, as a result of the reduced expression of TNFRs, to a different response of these cells to TNF-. These changes may be important in the evolution of the inflammatory process, potentially contributing to its transformation into a chronic and self-perpetuating process.

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