INABILITY OF HISTAMINE TO REGULATE TNF-ALPHA PRODUCTION BY HUMAN ALVEOLAR MACROPHAGES

Tumor necrosis factor alpha (TNF-a), a major product of alveolar macro phages: (AM), has been implicated in many pulmonary diseases. Histamin e, a mediator important in pulmonary inflammation, has been demonstrat ed to regulate the production of TNF-alpha by monocytes. Ln this study , we show that human AM and monocytes differ in their responses to his tamine. Whereas histamine suppressed lipopolysaccharide (LPS)-stimulat ed TNF-alpha production by monocytes through a cAMP-dependent mechanis m, it had no effect on either cAMP levels or TNF-alpha production by A M. In contrast, both PGE(2) and IL-10 suppressed LPS-stimulated TNF-al pha production by AM and monocytes. The lack of response of AM to hist amine appears unique, as histamine suppressed LPS-stimulated TNF-alpha production by mononuclear cells isolated from sites of acute and chro nic inflammation, as well as from noninflammatory tissues, and by macr ophages differentiated in vitro. In the presence of the phosphodiester ase (PDE) inhibitor 3-isobutyl-1-methylxanthine, histamine increased c AMP levels in AM. Freshly isolated monocytes and AM did not differ in PDE activity, However, PDE activity in AM, but not in monocytes, was i ncreased 15 min after culture with histamine and may, in part, be resp onsible for the inability of histamine to suppress TNF-alpha productio n by AM. However, this increase was small and we hypothesize that addi tional mechanisms may contribute to the unresponsiveness of AM to hist amine. We suggest that the lack oi-response of AM to histamine may be important in the host defense function of AM in the distal lung.