The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1.
Caveolin-1 (cav-1), the principle structural protein of plasmalemmal caveolae, regulates inflammatory signaling processes originating at the membrane. We show that cav-1 bound to TLR4 and inhibited LPS-induced proinflammatory cytokine (TNF-alpha and IL-6) production in murine macrophages. Mutation analysis revealed a cav-1 binding motif in TLR4, essential for this interaction and for attenuation of proinflammatory signaling. Cav-1 was required for the anti-inflammatory effects of carbon monoxide (CO), a product of heme oxygenase-1 (HO-1) activity. CO augmented the cav-1/TLR4 interaction. Upon LPS stimulation, HO-1 trafficked to the caveolae by a p38 MAPK-dependent mechanism, where it down-regulated proinflammatory signaling. These results reveal an anti-inflammatory network involving cav-1 and HO-1.
Wang
Xiao Mei
XM
Division of Pulmonary, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Kim
Hong Pyo
HP
Nakahira
Kiichi
K
Ryter
Stefan W
SW
Choi
Augustine M K
AM
D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology*; D051242:Caveolin 1 / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*
D051242:Caveolin 1; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse