Constitutive repression of interleukin-1alpha in endothelial cells.
Activation of complement stimulates inflammation and provides an initial vigorous defense against infection. Insertion of the membrane attack complex in cell membranes of vascular endothelial cells induces changes in cell differentiation that promote coagulation, thrombosis, inflammation, and immunity. These changes are mediated by production of interleukin (IL)-1alpha by endothelial cells, which acts locally on endothelial cells to contain infection and promote healing of the affected site. In healthy tissues, however, promoting coagulation and inflammation would be dysphysiologic. Accordingly, endothelial cell activation by the membrane attack complex depends on both transcriptional regulation of IL-1alpha and availability of that cytokine to broadly modify endothelial cell physiology. Here, we report that the IL-1alpha gene contains a suppressor sequence that cooperates with histone modification to regulate production of IL-1alpha by endothelial cells. The suppressor sequence binds C/EBP (CCAAT enhancer-binding protein) family DNA-binding proteins isolated from the nucleus of quiescent endothelial cells. These results suggest constitutive suppression of IL-1alpha maintains quiescence of endothelium and that terminal complement complexes remove that suppression, allowing IL-1alpha transcription and, ultimately, activation of endothelium to proceed.
Brunn
Gregory J
GJ
Department of Surgery, Mayo Clinic College of Medicine, Rochester, Minn, USA.
Saadi
Soheyla
S
Platt
Jeffrey L
JL
D000107:Acetylation; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D053582:Interleukin-1alpha; D012097:Repressor Proteins; D003165:Complement System Proteins; D006655:Histone Deacetylases