The pleural space is a potential compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells in a number of respiratory diseases. In an attempt to understand one aspect of the inflammatory process in the pleural space, we compared the responses in three different diseases (congestive heart failure [CHF], tuberculosis [TB], and cancer). Large concentrations of interleukin-8 (IL-8) were detected in cancer and TB effusions, but not in CHF. Surprisingly, the concentration of IL-8 correlated best with lymphocyte recruitment and not with neutrophil recruitment. Pleural fluid from cancer and TB patients was chemotactic for lymphocytes, and this activity was partly blocked by an anti-IL-8 antibody in cancer and completely blocked in TB. To determine whether there was the potential for a chemotactic gradient into the pleural space, pleural effusion cells were analyzed for the expression of IL-8. Cells in the effusions of cancer patients expressed IL-8, whereas IL-8 could not be detected from the cells of TB and CHF effusions. To explore the possible role of pleural macrophages in the regulation of IL-8, pleural effusion cells were treated with culture supernatants from stimulated pleural macrophages. Stimulated pleural macrophages were able to induce expression of messenger RNA (mRNA) for IL-8 and IL-8 protein production, and this activity was abrogated by blocking tumor necrosis factor-α. These findings suggest that soluble IL-8 is an important factor for the recruitment of lymphocytes into the pleural space, and that this cytokine is produced by both pleural structural and cancer cells after their activation by macrophage-derived, cytokine-mediated signals.