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-γ-induced activation of alveolar macrophages (aMϕs) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aMϕs stimulated with IFN-γ, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A's ability to bind to IFN-γ or IFN-γR1. We found that SP-A inhibited (IFN-γ + LPS)-induced TNF-α, iNOS, and CXCL10 production by rat aMϕs. When rat macrophages were stimulated with LPS and IFN-γ separately, SP-A inhibited both LPS-induced signaling and IFN-γ-elicited STAT1 phosphorylation. SP-A also decreased TNF-α and CXCL10 secretion by ex vivo-cultured human aMϕs and M-CSF-derived macrophages stimulated by either LPS or IFN-γ or both. Hence, SP-A inhibited upregulation of IFN-γ-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-γ (KD = 11 ± 0.5 nM) in a Ca(2+)-dependent manner and prevented IFN-γ interaction with IFN-γR1 on human aMϕs. We conclude that SP-A inhibition of (IFN-γ + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-γ abrogates IFN-γ effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.