Alveolar macrophage inhibition of lung-associated NK activity: involvement of prostaglandins and transforming growth factor-beta 1.

Abstract

Natural killer (NK) activity plays an important role in host defense. It is likely that this defensive role is shaped by compartmental and local environmental factors. The present study investigated the regulatory effects of alveolar macrophages (AM) on lung-associated NK activity. AM and lung lymphocytes (LL) were permitted to interact in a two-chamber system which prohibited cell contact but supported diffusion of soluble factors. AM were found to inhibit NK activity from LL in a time-dependent and reversible manner. The inhibitory event was shown to be mediated by soluble factors acting upon a post-binding event(s) in the lytic pathway of LL. AM inhibition was sensitive to indomethacin treatment (10(-5) M), which caused a decrease in prostaglandin E2 (PGE2) concentrations. Quantitation of PGE2 levels and treatment of LL with exogenous PGE2 indicated that the inhibitory effect could not be exclusively due to PGE2. It was subsequently found that exogenous transforming growth factor-beta 1 (TGF-beta 1) also inhibited LL NK activity and that treatment of inhibitory AM supernatant with a neutralizing antibody to TGF-beta 1 adsorbs up to 55% of its inhibitory activity. Moreover, the amount of TGF-beta 1 found in AM-LL co-culture media (25 pg/mL) correlated well with the level of NK inhibition observed. By contrast, platelet-derived growth factor and nitric oxide did not play a significant role in mediating AM suppression. Taken together, the data suggest that AM inhibit lung NK activity by interfering with post-binding lytic event(s) through the production of PGE2 and TGF-beta 1.