Zymosan and carrageenan represent two inflammatory stimuli leading to significant neutrophilia when injected into mice. Despite several similarities between the two proinflammatory agents, the mechanisms leading to neutrophil influx into the site of stimulus injection are unclear. As demonstrated by antibody (Ab) studies directed against adhesion molecules, L-selectin was pivotal for zymosan-induced but not carrageenan-induced pleurisy. Zymosan but not carrageenan injection into the pleural cavity caused blood neutrophilia and significant release of neutrophils from the bone marrow, events that were inhibited by anti-L-selectin but not anti-Mac-1 Ab pretreatment. Pertussis toxin, known to regulate cell efflux, abrogated both zymosan- and carrageenan-induced pleurisy, but only zymosan-induced neutrophil release from the bone marrow. Dexamethasone, known to inhibit pleurisy induced by either stimulus, had no effect on bone marrow neutrophil numbers. The G(i/o) G protein-coupled H4 histamine receptor is highly expressed in the bone marrow and on leukocytes and plays an important role in zymosan-induced pleurisy in vivo. Zymosan-triggered neutrophil release from bone marrow was abrogated by pretreatment of mice with thioperamide, a known H(3/4) receptor antagonist, whereas H1 and H2 receptor antagonists had no effect. Moreover, histamine itself, when injected intravenously, led to a similar time- and dose-dependent decrease of neutrophil numbers in the bone marrow that was inhibited by thioperamide. Because the H3 receptor is not expressed on neutrophils, these findings indicate that both H4 and L-selectin regulate zymosan-induced neutrophil release from bone marrow and subsequent infiltration in the pleurisy model.