TNF-Induced Haptoglobin Release from Human Neutrophils: Pivotal Role of the TNF p55 Receptor

Abstract

AbstractHaptoglobin (Hp), TNF-α, and neutrophils are parts of a highly interactive ensemble participating in inflammatory processes. Hp is taken up by neutrophils, stored within a cytoplasmic granular compartment, and is secreted during phagocytosis by those cells. In the present study, the effects of TNF-α on the release of Hp from human neutrophils were investigated. Incubation of neutrophils with TNF-α induced the release of Hp from cells in a time- and concentration-dependent manner as revealed by Western blot analysis and immunofluorescence. The release of Hp induced by TNF-α was not due to nonspecific lysis of the cells. TNF-α is a highly pleiotropic cytokine that mediates its effects by binding to two distinct receptors (p55 and p75). Administration of TNF-α mutants binding specifically either to the p55 or to the p75 TNF receptors showed that there is a preference of TNF-α for the p55 receptor in the mediation of Hp release by neutrophils. A stimulated release of Hp was also induced by the chemotactic tripeptide fMLP. The TNF-α-induced release of Hp from neutrophils was inhibited by erbstatin, a tyrosine kinase inhibitor. These findings suggest that TNF-α may promptly increase the level of Hp at sites of infection or injury, leading to the modulation of the acute inflammatory response.