Soluble tumor necrosis factor (TNF) receptors p55 and p75 and interleukin-10 downregulate TNF-alpha activity during the lung response to silica particles in NMRI mice

We have found reduced activity of tumor necrosis factor (TNF)-alpha accompa nying resolving and fibrosing alveolitis induced in NMRI mice by mineral pa rticles (MnO2 and SiO2, respectively), which is in apparent contradiction t o the well-recognized proinflammatory and profibrotic activities of this cy tokine. The objective of this study was to examine the mechanisms involved in this paradoxical response in NMRI mice. Although lung tissue messenger R NA (mRNA) levels for TNF-alpha were transiently (up to 15 d) and persistent ly (up to 120 d) upregulated in the resolving and fibrosing models, respect ively, these changes were not accompanied by a parallel release of TNF-alph a protein, which was respectively transiently and persistently downregulate d in bronchoalveolar lavage fluid and bronchoalveolar lavage cell cultures. The downregulation of the TNF-alpha protein was concurrent with the accumu lation of recruited polymorphonuclear neutrophils (PMNs) in alveoli, and co culture experiments showed that PMN explanted from the lungs of mice treate d with silica particles were able to downregulate the expression of TNF-alp ha protein by naive alveolar macrophages. In addition, PMN depletion preven ted the downregulation of TNF-alpha induced by silica, further establishing the role of PMNs in the downregulation of TNF-alpha. The possible degradat ion of TNF-alpha by proteolytic enzymes could be excluded. Marked increases in soluble p55 and p75 TNF receptors (sTNF-R), as well as in interleukin ( lL)-10, paralleled the downregulation of TNF-alpha protein. The role of the se mediators in the observed reduction of TNF-alpha activity was confirmed by immunoneutralizing the activity of p55 and p75 sTNF-R and by using IL-10 -deficient animals. Because IL-10 also exerts profibrotic activity in addit ion to its antiinflammatory activity, the protracted overproduction of IL-1 0 observed in fi fibrosing alveolitis may help the understanding of why, in NMRI mice treated with silica particles, lung fibrosis develops in associa tion with a downregulation of TNF-alpha.