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.
Departamento de Bioquímica y Biología Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain;
Carlos M
CM
Minutti
Departamento de Bioquímica y Biología Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain;
Belén
0000-0002-9558-3020
B
García-Fojeda
Departamento de Bioquímica y Biología Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain;
Alejandra
A
Sáenz
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and.
Mateo
M
de Las Casas-Engel
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; Departamento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, 08036 Barcelona, Spain.
Raquel
0000-0001-6960-0985
R
Guillamat-Prats
Departamento de Bioquímica y Biología Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain;
Alba
A
de Lorenzo
Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; Departamento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, 08036 Barcelona, Spain.
Anna
0000-0002-4990-8162
A
Serrano-Mollar
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain; and.
Ángel L
ÁL
Corbí
Departamento de Bioquímica y Biología Molecular I, Universidad Complutense de Madrid, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; ccasalsc@ucm.es.
Cristina
0000-0003-2696-0918
C
Casals
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D037662:Pulmonary Surfactant-Associated Protein A / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D037662:Pulmonary Surfactant-Associated Protein A; D017471:Receptors, Interferon; D007371:Interferon-gamma