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Tumor necrosis factor alpha (TNF-α), a major product of alveolar macrophages (AM), has been implicated in many pulmonary diseases. Histamine, a mediator important in pulmonary inflammation, has been demonstrated to regulate the production of TNF-α by monocytes. In this study, we show that human AM and monocytes differ in their responses to histamine. Whereas histamine suppressed lipopolysaccharide (LPS)-stimulated TNF-α production by monocytes through a cAMP-dependent mechanism, it had no effect on either cAMP levels or TNF-α production by AM. In contrast, both PGE2 and IL-10 suppressed LPS-stimulated TNF-α production by AM and monocytes. The lack of response of AM to histamine appears unique, as histamine suppressed LPS-stimulated TNF-α production by mononuclear cells isolated from sites of acute and chronic inflammation, as well as from noninflammatory tissues, and by macrophages differentiated in vitro. In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1- methylxanthine, histamine increased cAMP levels in AM. Freshly isolated monocytes and AM did not differ in PDE activity. However, PDE activity in AM, but not in monocytes, was increased 15 min after culture with histamine and may, in part, be responsible for the inability of histamine to suppress TNF-α production by AM. However, this increase was small and we hypothesize that additional mechanisms may contribute to the unresponsiveness of AM to histamine. We suggest that the lack of response of AM to histamine may be important in the host defense function of AM in the distal lung.