TY - JOUR
T1 - Different expression of TNF-α receptors and prostaglandin E2 production in normal and fibrotic lung fibroblasts. Potential implications for the evolution of the inflammatory process
AU - Vancheri, Carlo
AU - Sortino, Maria Angela
AU - Tomaselli, Valerio
AU - Mastruzzo, Claudio
AU - Condorelli, Fabrizio
AU - Bellistrí, Guglielmo
AU - Pistorio, Maria P.
AU - Canonico, Pier Luigi
AU - Crimi, Nunzio
PY - 2000
Y1 - 2000
N2 - Normal human lung fibroblasts downregulate the production of tumor necrosis factor (TNF)-α 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-α by lipopolysaccharide (LPS)-activated monocytes. The percentage of inhibition induced by normal cells on the production of TNF-α 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-α 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-α on some functions associated with collagen metabolism in NF and FF showed an increase of the expression of the receptor for collagen type I (α2β1 integrin) in NF (42 ± 10%) and an even larger increase in FF (102 ± 23%) (P < 0.05). Interestingly, unlike NF, TNF-α 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-α treatment may lead to an unrestrained release of TNF-α from activated monocytes and, as a result of the reduced expression of TNFRs, to a different response of these cells to TNF-α. These changes may be important in the evolution of the inflammatory process, potentially contributing to its transformation into a chronic and self-perpetuating process.
AB - Normal human lung fibroblasts downregulate the production of tumor necrosis factor (TNF)-α 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-α by lipopolysaccharide (LPS)-activated monocytes. The percentage of inhibition induced by normal cells on the production of TNF-α 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-α 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-α on some functions associated with collagen metabolism in NF and FF showed an increase of the expression of the receptor for collagen type I (α2β1 integrin) in NF (42 ± 10%) and an even larger increase in FF (102 ± 23%) (P < 0.05). Interestingly, unlike NF, TNF-α 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-α treatment may lead to an unrestrained release of TNF-α from activated monocytes and, as a result of the reduced expression of TNFRs, to a different response of these cells to TNF-α. These changes may be important in the evolution of the inflammatory process, potentially contributing to its transformation into a chronic and self-perpetuating process.
UR - http://www.scopus.com/inward/record.url?scp=0034038206&partnerID=8YFLogxK
U2 - 10.1165/ajrcmb.22.5.3948
DO - 10.1165/ajrcmb.22.5.3948
M3 - Article
SN - 1044-1549
VL - 22
SP - 628
EP - 634
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 5
ER -