Differential regulation of endothelial cell activation by complement and interleukin 1alpha.
Activation of complement on endothelium triggers physiological changes that promote coagulation, thrombosis, and inflammation. Unlike agonists such as cytokines and endotoxin that induce these changes through transcription of many genes, complement, particularly the membrane attack complex, primarily induces release of IL-1alpha by the endothelial cells; the cytokine may then be removed by normal blood flow or may promote activation of the full range of endothelial cell responses in an autocrine or paracrine manner. We studied the intracellular signaling pathways used by complement to activate interleukin (IL)-1alpha transcription in cultured endothelial cells. The membrane attack complex and other pore-forming proteins stimulated calcineurin and activated selective transcription of the IL-1alpha gene. In contrast, the action of cytokines such as IL-1alpha was not selective and not dependent on calcineurin activity. Transcription of IL-1alpha, whether stimulated by complement and calcineurin or by "conventional agonists," such as IL-1alpha independent of calcineurin, proceeded via binding of nuclear factor kappaB transcriptional activators to the IL-1alpha gene promoter. These findings define a molecular mechanism through which complement regulates IL-1alpha production by endothelial cells and explain how blood flow may determine the extent of complement-stimulated inflammation.
Brunn
Gregory J
GJ
Transplantation Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Saadi
Soheyla
S
Platt
Jeffrey L
JL
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D019040:E-Selectin / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D013552:Swine; D014158:Transcription, Genetic
D015938:Complement Membrane Attack Complex; D019040:E-Selectin; D007375:Interleukin-1; D016328:NF-kappa B; D003165:Complement System Proteins; D011493:Protein Kinase C; D019703:Calcineurin; D002118:Calcium