Am. J. Respir. Cell Mol. Biol., Vol 15, No. 4, 10 1996, 460-466.
Human lung fibroblasts inhibit tumor necrosis factor-alpha production by LPS-activated monocytes
C Vancheri, N Crimi, E Conte, MP Pistorio, C Mastruzzo, M Lamicela, A Messina and A Mistretta
Institute of Respiratory Diseases, University of Catania, Italy.
Mononuclear phagocytes are important regulators of normal immune,
inflammatory, and fibrotic responses. These functions are mediated through
the production of several cytokines, including tumor necrosis factor-alpha
(TNF-alpha), which regulate the activity of inflammatory and tissue
structural cells such as fibroblasts. It is increasingly evident that
fibroblasts are also capable of releasing a number of cytokines and soluble
factors that can, in turn, interact with monocytes and thereby modulate the
inflammatory process. In this study we provide evidence that human lung
fibroblasts, through the release of soluble factors such as prostaglandin
E2 (PGE2), inhibit both TNF messenger ribonucleic acid (mRNA) accumulation
and TNF-alpha protein release by lipopolysaccharide (LPS)-activated human
peripheral blood monocytes (PBM). Reverse transcriptase-polymerase chain
reaction (RT- PCR) results showed that fibroblast-conditioned medium (FCM)
caused a 50% reduction of the TNF-alpha transcript accumulation in LPS-
stimulated monocytes. Furthermore, FCM induced a significant decrease in
the release of TNF-alpha by LPS-activated PBM. This effect was dependent on
the concentration of the FCM and the number of fibroblasts producing it.
The maximal effect was seen with monocytes cultured in 100% FCM produced by
2 x 10(6) fibroblasts. This indicated that one or possibly more soluble
factors released by fibroblasts were responsible for the effect.
Considering that exogenous PGE2 can inhibit TNF-alpha production by PBM,
and that fibroblasts are a good source of PGE2, we determined the content
of PGE2 in the FCM used in our experiments. We found a good correlation (r
= 0.949) between the amount of PGE2 produced by fibroblasts and the degree
of TNF-alpha inhibition exerted. In addition, the inhibitory effect of FCM
was mimicked by the addition to PBM cultures of exogenous PGE2 in amounts
similar to those spontaneously released by fibroblasts in FCM. All of these
data suggest a molecular and cellular interaction between PBM and
fibroblasts that could contribute to those modulatory mechanisms involved
in the self- limitation of the fibrotic process.
