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.

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.

Regional manifestations and control of the immune system.

Although immune responses are generally considered to be systemic, local events such as interaction of complement products with blood vessels and with inflammatory cells play a pivotal role in determining the nature and manifestations of immune responses. This paper will discuss how blood vessel physiology and immunity influence one another to reach homeostasis upon exposure to an infectious agent. We review new insights into the mechanisms by which the microenvironment of tissues protects against microbial invasion yet facilitates migration of leukocytes and 'decides' whether immunity or tolerance ensues and whether, in the face of immunity, protective responses or tissue injury ensues. These 'decisions' are made based on interaction of components of normal tissues such as proteoglycans and injured tissues such as cell-associated cytokines with receptors on immune cells and blood vessels.

Pathways to acute humoral rejection.

Acute humoral rejection, also known as acute vascular rejection, is a devastating condition of organ transplants and a major barrier to clinical application of organ xenotransplantation. Although initiation of acute humoral or vascular rejection is generally linked to the action of antibodies and complement on the graft, other factors such as ischemia, platelets, T cells, natural killer cells, and macrophages have also been implicated. Central to any understanding of the pathogenesis of acute humoral rejection, and to developing means of preventing it, is to know whether these factors injure the graft independently or through one or few pathways. We addressed this question by examining early events in a severe model of vascular rejection in which guinea pig hearts transplanted heterotopically into rats treated with cobra venom factor (CVF) develop disease over 72 hours. The early steps in acute vascular rejection were associated with expression of a set of inflammatory genes, which appeared to be controlled by availability of interleukin (IL)-1. Interruption of IL-1 signaling by IL-1 receptor antagonist (IL-1ra) averted expression of these genes and early tissue changes, including coagulation and influx of inflammatory cells. These findings suggest IL-1 plays an important role in initiation of acute humoral rejection.