Surfactant blocks lipopolysaccharide signaling by inhibiting both mitogen-activated protein and IkappaB kinases in human alveolar macrophages.
Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) from gram-negative bacteria is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome and pneumonia, among others. Our previous studies demonstrated that the clinically used, natural surfactant product Survanta inhibited proinflammatory cytokine secretion from LPS-stimulated human alveolar macrophages. Here we investigated the effect of Survanta on mitogen-activated protein (MAP) and IkappaB kinases. Survanta blocked LPS-induced activation of nuclear factor-kappaB, a key regulatory transcription factor involved in cytokine production, by preventing phosphorylation of IkappaBalpha, and its subsequent degradation. IkappaB is phosphorylated by specific kinases (IKK) before degradation. Survanta inhibited activity of both alpha and beta subunits of IKK, thereby delaying the phosphorylation of IkappaB. Interestingly, IKK-alpha is predominant in alveolar macrophages, whereas IKK-beta predominates in monocytes. Survanta also inhibited extracellular signal-regulated kinase and p38 MAP kinase activity induced by LPS. Data are the first to show that surfactant may regulate lung homeostasis in part by inhibiting proinflammatory cytokine production through reduction of IKK and MAP kinase activity.
Raychaudhuri
Baisakhi
B
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Abraham
Susamma
S
Bonfield
Tracey L
TL
Malur
Anagha
A
Deb
Amitabha
A
DiDonato
Joseph A
JA
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D001688:Biological Products / Q000378:metabolism / Q000494:pharmacology*; D054407:Chemokine CCL4; D006706:Homeostasis; D006801:Humans; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D001688:Biological Products; D054407:Chemokine CCL4; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020928:Mitogen-Activated Protein Kinases; C072197:beractant