The cytoplasmic domain of tissue factor restricts physiological albuminuria and pathological proteinuria associated with glomerulonephritis in mice.

Background/aims: Tissue factor (TF) is a transmembrane protein that is essential for coagulation. TF is expressed on podocytes and its cytoplasmic domain has cell signalling functions in epithelial cells.

Methods: Mice lacking the cytoplasmic domain of TF (TF(CT-/-) mice) were used to study its role in physiological albuminuria and pathological proteinuria following induction of glomerulonephritis (GN).

The cytoplasmic domain of tissue factor in macrophages augments cutaneous delayed-type hypersensitivity.

In addition to its procoagulant role, tissue factor (TF) has important coagulation-independent roles, including in inflammation. The cytoplasmic domain of TF has been implicated in some of these coagulation-independent roles, particularly cell signaling. To assess the contribution of the cytoplasmic domain of TF to cell-mediated adaptive immunity, the development of cutaneous delayed-type hypersensitivity (DTH) was studied in mice lacking the cytoplasmic domain of TF (TF(deltaCT/deltaCT) mice).

Leukocytes in glomerular injury.

Leukocytes of the innate immune system play a central protective role in immune defense to pathogens but may also mediate injurious inflammatory responses resulting in tissue injury. These leukocytes provide the first rapid cellular defense mechanisms through a limited repertoire of rapid pre-programmed responses, but they are also involved in chronic inflammation and tissue repair. They are directed to sites of pathogen challenge and inflammation by a variety of mechanisms and are activated in response to both exogenous and endogenous stimuli.

Protease-activated receptor-2 augments experimental crescentic glomerulonephritis.

Protease-activated receptor-2 (PAR-2) is a cellular receptor expressed prominently on epithelial, mesangial, and endothelial cells in the kidney and on macrophages. PAR-2 is activated by serine proteases such as trypsin, tryptase, and coagulation factors VIIa and Xa. It induces pleiotropic effects including vasodilatation, increasing plasminogen activator inhibitor (PAI-1) expression, mesangial cell proliferation, and cytokine production by macrophages.

Cytokines in glomerulonephritis.

Cytokines play central roles in both innate and adaptive immune responses that lead to renal inflammation. They are involved systemically in cross-talk between antigen-presenting cells, leukocytes, and regulatory cells to initiate and modulate nephritogenic immunity. Within the kidney, cytokines play a central role in signaling between infiltrating leukocytes and intrinsic renal cells and orchestrate the effector responses that lead to renal damage.

T cells in crescentic glomerulonephritis.

Crescent formation in glomerulonephritis (GN) is a manifestation of severe glomerular injury that usually results in a poor clinical outcome. In humans, crescentic GN is frequently associated with evidence of either systemic or organ-specific autoimmunity. T cells play a major role in initiation of adaptive immune responses that lead to crescentic injury.

A pathogenetic role for mast cells in experimental crescentic glomerulonephritis.

Mast cells infiltrate kidneys of humans with crescentic glomerulonephritis (GN), and the degree of infiltrate correlates with outcome. However, a functional role for mast cells in the pathogenesis of GN remains speculative. GN was induced by intravenous administration of sheep anti-mouse glomerular basement membrane globulin.

Conditional ablation of macrophages halts progression of crescentic glomerulonephritis.

The presence of macrophages in inflamed glomeruli of rat kidney correlates with proliferation and apoptosis of resident glomerular mesangial cells. We assessed the contribution of inflammatory macrophages to progressive renal injury in murine crescentic glomerulonephritis (GN). Using a novel transgenic mouse (CD11b-DTR) in which tissue macrophages can be specifically and selectively ablated by minute injections of diphtheria toxin, we depleted renal inflammatory macrophages through days 15 and 20 of progressive crescentic GN.

Contributions of intrinsic renal cells to crescentic glomerulonephritis.

The pro-inflammatory contributions of leukocytes, particularly macrophages and T cells, to the immunopathogenesis of proliferative forms of glomerulonephritis (GN) have been clearly established by various techniques, including in vivo depletion studies in experimental models. The evidence for an active pro-inflammatory role for intrinsic renal cells in GN has relied on studies demonstrating their production of pro-inflammatory mediators in vitro and during the development of GN. Until recently,the specific in vivo contributions of mediators from intrinsic renal cells to inflammatory injury in GN have proven difficult to define.

Resident kidney cells and their involvement in glomerulonephritis.

Each year, worldwide, there is an increasing number of patients with chronic kidney disease that progress to end-stage renal disease. Glomerulonephritis (GN) is the commonest single cause of end-stage renal failure in the world. GN can be a manifestation of primary renal injury or may be a secondary feature of a systemic disease process, for example Systemic Lupus Erythematosus (SLE) and Anti-Neutrophilic Cytoplasmic Antibody (ANCA) associated vasculitis.

Granulocyte macrophage colony-stimulating factor expression by both renal parenchymal and immune cells mediates murine crescentic glomerulonephritis.

GM-CSF has previously been demonstrated to be important in crescentic glomerulonephritis (GN). As both renal parenchymal cells and infiltrating inflammatory cells produce GM-CSF, their separate contributions to inflammatory renal injury were investigated by creation of two different types of GM-CSF chimeric mice: (1) GM-CSF-deficient (GM-CSF-/-)-->wild-type (WT) chimeras with leukocytes that are unable to produce GM-CSF and (2) WT-->GM-CSF-/- chimeras with deficient renal cell GM-CSF expression. Crescentic anti-glomerular basement membrane GN was induced in WT, GM-CSF(-/-)-->WT chimeras, WT-->GM-CSF-/- chimeras, and GM-CSF-/- mice by planting an antigen (sheep globulin) in their glomeruli.

CD80 and CD86 costimulatory molecules regulate crescentic glomerulonephritis by different mechanisms.

Background: CD80 and CD86 costimulatory molecules have been shown to affect the induction of Th1-mediated crescentic antiglomerular basement membrane (GBM) antibody-initiated glomerulonephritis (GN). The aim of the current studies was to define the mechanisms by which CD80 and CD86 regulate the development of this disease.

Methods: Anti-GBM GN was induced in CD80-/-, CD86-/-, and CD80/86-/- mice, as well as in C57BL/6 controls.

Glomerular expression of CD80 and CD86 is required for leukocyte accumulation and injury in crescentic glomerulonephritis.

The participation of renal expression of CD80 and CD86 in the immunopathogenesis of crescentic Th1-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) has not been assessed. Immunohistochemical staining demonstrated prominent upregulation of both molecules in glomeruli of mice with anti-GBM GN, suggesting a potential role for the local expression of CD80 and CD86 in nephritogenic effector T cell responses. For testing this hypothesis, control or inhibitory anti-CD80 and/or anti-CD86 mAb were administered to mice during the effector phase of the disease but after the establishment of a systemic immune response.

IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment.

Experimental crescentic glomerulonephritis (GN) is characterized by T helper 1 (Th1) directed nephritogenic immune responses and cell-mediated glomerular injury. IL-12p40, the common cytokine chain for both IL-12 and IL-23, is important in the generation and potentially the maintenance of Th1 responses, whereas IL-18 is a co-factor for Th1 responses that may have systemic and local proinflammatory effects. For testing the hypothesis that both endogenous IL-12p40 and endogenous IL-18 play pathogenetic roles in crescentic GN, accelerated anti-glomerular basement membrane GN was induced in mice genetically deficient in IL-12p40 (IL-12p40-/-), IL-18 (IL-18-/-), or both IL-12p40 and IL-18 (IL-12p40-/-IL-18-/-).

Endogenous IL-13 limits humoral responses and injury in experimental glomerulonephritis but does not regulate Th1 cell-mediated crescentic glomerulonephritis.

IL-13 is produced by T helper 2 (Th2) cells, has a role in stimulating Th2-mediated injury, alters humoral responses, and may directly suppress macrophage and neutrophil function. In immune renal disease, the engagement of different effector mediator systems, including humoral and cell-mediated effectors, can result in glomerular injury. Experimental crescentic glomerulonephritis (known as autologous anti-glomerular basement membrane glomerulonephritis) induced by planting an antigen in glomeruli of mice is Th1 directed, delayed-type hypersensitivity (DTH)-like, and antibody independent.

Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis.

Background: Tissue factor initiated glomerular fibrin deposition is an important mediator of injury in crescentic glomerulonephritis. Recent data have suggested noncoagulant roles for tissue factor in inflammation.

Methods: To test the hypothesis that in addition to its effects in initiating coagulation, tissue factor has proinflammatory effects in glomerulonephritis, rabbits given crescentic anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis were defibrinogenated with ancrod.

The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia.

Tissue factor (TF) is an integral membrane protein that binds factor VIIa and initiates coagulation. The extracellular domain of TF is responsible for its hemostatic function and by implication in the dysregulation of coagulation, which contributes to death in endotoxemia. The role of the cytoplasmic domain of tissue factor in endotoxemia was studied in mice, which lack the cytoplasmic domain of TF (TF(deltaCT/deltaCT)).

An IL-12-independent role for CD40-CD154 in mediating effector responses: studies in cell-mediated glomerulonephritis and dermal delayed-type hypersensitivity.

Crescentic glomerulonephritis (GN) results from IL-12-driven Th1-directed cell-mediated responses (akin to delayed-type hypersensitivity (DTH)) directed against glomerular Ags. CD40-CD154 interactions are critical for IL-12 production and Th1 polarization of immune responses. Crescentic anti-glomerular basement membrane GN was induced in C57BL/6 (wild-type (WT)) mice (sensitized to sheep globulin) by planting this Ag (as sheep anti-mouse glomerular basement membrane globulin) in their glomeruli.

Leukocyte-derived interleukin-1beta interacts with renal interleukin-1 receptor I to promote renal tumor necrosis factor and glomerular injury in murine crescentic glomerulonephritis.

The involvement of proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) in crescentic glomerulonephritis (GN) is well established. Recently the requirement of intrinsic renal cell participation via their production of TNF in crescentic GN was demonstrated. The current studies address the relative contributions of leukocyte and intrinsic renal cell-derived IL-1beta in the induction of TNF production and glomerular injury by studying bone marrow chimeric mice.

Contributions of IL-1beta and IL-1alpha to crescentic glomerulonephritis in mice.

ABSTRACT. Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1alpha and IL-1beta) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1beta have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1alpha has received little attention.

Intrinsic renal cell expression of CD40 directs Th1 effectors inducing experimental crescentic glomerulonephritis.

Evidence suggests that human and experimental crescentic GN results from Th1-predominant immunity to glomerular antigens. CD40/CD154 signaling plays a key role in initiating Th1 responses and may direct Th1 effector responses. The role of CD40 in the development of GN was assessed in murine experimental anti-glomerular basement membrane GN.

The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice.

Accumulation of T cells and macrophages in atherosclerotic plaques and the formation of antibodies directed against plaque proteins suggests that adaptive immunity contributes to the development of atherosclerosis. The contribution of Th1 and Th2 helper cell subsets to atherogenesis was studied in a murine model by interbreeding apolipoprotein E-deficient (apoE(-/-)) mice with mice deficient in key cytokines that drive either Th1 responses [interleukin (IL)-12] or Th2 responses (IL-4). Compared to apoE(-/-) mice, apoE(-/-)/IL-12(-/-) mice had a 52% reduction in plaque area in the aortic root at 30 weeks of age (P < 0.