Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice.
Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.
Carrithers
Michael
M
Department of Neurology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.
Tandon
Suman
S
Canosa
Sandra
S
Michaud
Michael
M
Graesser
Donnasue
D
Madri
Joseph A
JA
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004198:Disease Susceptibility; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology*; D011652:Pulmonary Circulation; D050796:STAT3 Transcription Factor; D012772:Shock, Septic / Q000473:pathology*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014638:Vanadates / Q000494:pharmacology
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D014638:Vanadates