Early production of tumor necrosis factor-α by Gr-1⁺ cells and its role in the host defense to pneumococcal infection in lungs

In this study, we elucidated the role of tumor necrosis factor (TNF)-α in the host defense to pulmonary infection with Streptococcus pneumoniae and defined the cellular source of this cytokine at an early stage of infection. Administration of anti-TNF-α monoclonal antibody (mAb) resulted in the reduced accumulation of neutrophils in bronchoalveolar lavage fluids (BALFs) and severe exacerbation of this infection. In a flow cytometric analysis, the intracellular expression of TNF-α was detected in Gr-1 ^bright+ and Gr-1^dull+ cells during the time intervals postinfection, and F4/80⁺ cells expressed intracellular TNF-α before Gr-1^dull+ cells appeared. The Gr-1^bright+ and Gr-1^dull+ cells sorted from BALF cells at 24 h were identified as neutrophils and macrophage-like cells, respectively, and the Gr-1 ^dull+ cells expressing CD11c, partially CD11b and a marginal level of F4/80 secreted TNF-α in in vitro cultures. Finally, deletion of Gr-1 ⁺ cells by administration of the specific mAb significantly reduced the concentrations of this cytokine in BALF at 6 and 12 h postinfection, but not the expression of TNF-α in F4/80⁺ cells. Thus, these results demonstrated that neutrophils, F4/80⁺ macrophages and Gr-1 ^dull+ CD11c⁺ macrophage-like cells played an important role in the production of TNF-α in lungs at an early stage of infection with S. pneumoniae.