Surfactant protein A decreases nitric oxide production by macrophages in a tumor necrosis factor-alpha-dependent mechanism.

Abstract

Surfactant protein A (SP-A) modulates the lung defense system through regulation of cytokines and nitric oxide (NO) production by alveolar macrophages (AMs). Whether SP-A upregulates or downregulates production of proinflammatory cytokines and NO is controversial. This study demonstrates the molecular mechanism(s) by which SP-A suppresses NO production by activated murine AMs. NO production by interferon-gamma (IFN-gamma) and IFN-gamma plus Mycobacterium avium-stimulated AMs was mediated through tumor necrosis factor-alpha (TNF-alpha) production, as addition of neutralizing anti-TNF-alpha antibodies during AMs stimulation resulted in reduced NO production. SP-A suppressed NO production by activated AMs by inhibiting TNF-alpha production. The maximum inhibitory effect of SP-A on NO production was observed at 20 microg/ml of SP-A concentration. Furthermore, SP-A inhibited activation of nuclear factor-kappa B, a transcription factor required for induction of TNF-alpha and inducible NO synthase genes. These findings suggest that SP-A suppresses NO production by activated AMs by inhibiting TNF-alpha secretion and nuclear factor-kappa B activation. This study also highlights the importance of SP-A levels in the lung, as changes in SP-A levels may modulate the local lung defense system.