Surfactant Protein A Prevents IFN-γ/IFN-γ Receptor Interaction and Attenuates Classical Activation of Human Alveolar Macrophages

Lung surfactant protein A (SP-A) plays an important function in modulating inflammation in the lung. However, the exact role of SP-A and the mechanism by which SP-A affects IFN-gamma-induced activation of alveolar macrophages (aM phi s) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aM phi s stimulated with IFN-gamma, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A's ability to bind to IFN-gamma or IFN-gamma R1. We found that SP-A inhibited (IFN-gamma + LPS)-induced TNF-alpha, iNOS, and CXCL10 production by rat aM phi s. When rat macrophages were stimulated with LPS and IFN-gamma separately, SP-A inhibited both LPS-induced signaling and IFN-gamma-elicited STAT1 phosphorylation. SP-A also decreased TNF-alpha and CXCL10 secretion by ex vivo-cultured human aM phi s and M-CSF-derived macrophages stimulated by either LPS or IFN-gamma or both. Hence, SP-A inhibited upregulation of IFN-gamma-inducible genes (CXCL10, RARRES3, and ETV7) as well as STAT1 phosphorylation in human M-CSF-derived macrophages. In addition, we found that SP-A bound to human IFN-gamma (K-D = 11 +/- 0.5 nM) in a Ca2+-dependent manner and prevented IFN-gamma interaction with IFN-gamma R1 on human aM phi s. We conclude that SP-A inhibition of (IFN-gamma + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-gamma abrogates IFN-gamma effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.