Human lung fibroblasts inhibit tumor necrosis factor-alpha production by LPS-activated monocytes

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.