Soluble Tumor Necrosis Factor (TNF) Receptors p55 and p75 and Interleukin-10 Downregulate TNF-α Activity during the Lung Response to Silica Particles in NMRI Mice

We have found reduced activity of tumor necrosis factor (TNF)-alpha accompanying resolving and fibrosing alveolitis induced in NMRI mice by mineral particles (MnO2 and SiO2, respectively), which is in apparent contradiction to the well-recognized proinflammatory and profibrotic activities of this cytokine. The objective of this study was to examine the mechanisms involved in this paradoxical response in NMRI mice. Although lung tissue messenger RNA (mRNA) levels for TNF-alpha were transiently (up to 15 d) and persistently (up to 120 d) upregulated in the resolving and fibrosing models, respectively, these changes were not accompanied by a parallel release of TNF-alpha protein, which was respectively transiently and persistently downregulated in bronchoalveolar lavage fluid and bronchoalveolar lavage cell cultures. The downregulation of the TNF-alpha protein was concurrent with the accumulation of recruited polymorphonuclear neutrophils (PMNs) in alveoli, and coculture experiments showed that PMN explanted from the lungs of mice treated with silica particles were able to downregulate the expression of TNF-alpha protein by naive alveolar macrophages. In addition, PMN depletion prevented the downregulation of TNF-alpha induced by silica, further establishing the role of PMNs in the downregulation of TNF-alpha. The possible degradation 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 (IL)-10, paralleled the downregulation of TNF-alpha protein. The role of these 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 addition to its antiinflammatory activity, the protracted overproduction of IL-10 observed in fibrosing alveolitis may help the understanding of why, in NMRI mice treated with silica particles, lung fibrosis develops in association with a downregulation of TNF-alpha.