Endothelial Cell Activation by Pore-Forming Structures

Saadi, Soheyla; Holzknecht, Robert A.; Patte, Christian P.; Platt, Jeffrey L.

doi:10.1161/01.cir.101.15.1867

Cited by 85 publications

(75 citation statements)

References 28 publications

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“…For example, exposure of endothelial cells to TNF-␣ induces IB, which inhibits NFB activation (31). Consistent with this possibility, Saadi et al (32) found that complement activation on endothelial cells also induces IB expression. The third mechanism involves the up-regulation of protective proteins and pathways in response to a noxious agonist providing cells or tissues of a graft with a general resistance to the initial agonist as well as other unrelated stimuli.…”

Section: Accommodation Of the Graftmentioning

confidence: 81%

Accommodation: Preventing Injury in Transplantation and Disease

Koch¹,

Khalpey²,

Platt

2004

The Journal of Immunology

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127

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Humoral immunity, as a cause of damage to blood vessels, poses a major barrier to successful transplantation of organs. Under some conditions, humoral immunity causes little or no damage to an organ graft. We have referred to this condition, in which a vascularized graft functions in the face of humoral immunity directed against it, as “accommodation.” In this paper, we review changes in the graft and in the host that may account for accommodation, and we consider that what we call accommodation of organ grafts may occur widely in the context of immune responses, enabling immune responses to target infectious organisms without harming self-tissues.

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Section: Accommodation Of the Graftmentioning

confidence: 81%

Accommodation: Preventing Injury in Transplantation and Disease

Koch¹,

Khalpey²,

Platt

2004

The Journal of Immunology

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127

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“…In addition to mechanical injury, both hypoxia and sublytic complement deposition, which are stimuli relevant to solid organ transplantation, can induce EC release of IL-1␣ (70,71). Sublytic complement deposition allows for IL-1␣ release, independent of cell death, through disruption of the plasma membrane, either by generating membrane pores or by inducing membrane vesiculation (72,73). Also, inflammatory cytokines such as TNF and IL-1 itself cause EC to present bioactive IL-1␣ on their surface in a membrane-bound form (35).…”

Section: Discussionmentioning

confidence: 99%

IL-1α and IL-1β Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response

Rao¹,

Tracey

Pober

2007

The Journal of Immunology

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Preoperative or perioperative ischemic injury of allografts predisposes to graft arteriosclerosis, the major cause of late graft failure. We hypothesize that injured tissues release mediators that increase the production of pathogenic cytokines by alloreactive T cells. We find that freeze-thaw lysates of human endothelial cells (EC) increase both IFN-γ and IL-17 production by human CD4+ T cells activated by HLA-DR+ allogeneic EC. Immunoadsorption of high-mobility group box 1 protein (HMGB1) reduces this activity in the lysates by about one-third, and recombinant HMGB1 increases T cell cytokine production. HMGB1 acts by inducing IL-1β secretion from contaminating monocytes via TLR4 and CD14. Upon removal of contaminating monocytes, the remaining stimulatory activity of EC lysates is largely attributable to IL-1α. Recombinant IL-1 directly augments IFN-γ and IL-17 production by activated memory CD4+ T cells, which express IL-1R1. Furthermore, IL-1 increases the frequency of alloreactive memory CD4+ T cells that produce IL-17, but not those that produce IFN-γ, in secondary cultures. Our results suggest that IL-1, released by injured EC or by HMGB1-stimulated monocytes, is a key link between injury and enhanced alloimmunity, offering a new therapeutic target for preventing late graft failure.

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“…First, MAC has been shown to cause proliferation of glomerular mesangial, endothelial, and epithelial cells in vitro and therefore may be directly involved in inducing a increase in intrinsic cell number (17,21,44,45). Additionally, there are data indicating that MAC can induce the synthesis and/or secretion of a number of proinflammatory cytokines such as TNF-␣ and IL-1 (22,44), adhesion molecules such as ICAM-1 and E selectin (23), and chemokines such as IL-8 (46) and that these effects may play a role in the infiltration of cells to the glomerulus. We have also demonstrated that later in the progression of ANTN, mCd59a deficiency, by allowing unregulated MAC deposition, exacerbates glomerular thrombosis.…”

Section: Discussionmentioning

confidence: 99%

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Turnberg¹,

Botto²,

Warren³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. CD59 is a complement regulatory protein that inhibits the terminal part of the complement system, the membrane attack complex (MAC), a mediator of renal injury. Mice deficient in the Cd59a gene (mCd59aϪ/Ϫ) were used to investigate the role of CD59 in experimentally induced accelerated nephrotoxic nephritis, a model of immune complex-mediated glomerulonephritis. After accelerated nephrotoxic nephritis was induced by administration of sheep nephrotoxic globulin, mCd59aϪ/Ϫ mice and strain-matched controls on two genetic backgrounds, 129/Sv ϫ C57BL/6 and 129/Sv, were examined. For both, mCd59aϪ/Ϫ mice developed significantly greater glomerular cellularity than wild-type (WT) mice at day 5 after administration. At day 10 post-administration, mCd59aϪ/Ϫ mice exhibited more glomerular thrombosis than WT mice (thrombosis score, 1.8 [range, 1.4 to 4.0] versus 0.8 [range, 0.2 to 1.5] quadrants thrombosed per glomerulus, respectively; P ϭ 0.0006). In the majority of experiments, mCd59aϪ/Ϫ mice also had significantly more proteinuria than controls; however, there was no difference in serum creatinine or albumin. Quantitative immunofluorescence of kidney sections revealed significantly more C9 (as a marker of MAC) deposition within glomeruli of mCd59aϪ/Ϫ mice than WT controls (P Ͻ 0.001). There was no difference in deposition of C3 and sheep IgG between the two experimental groups. The lack of CD59a, by allowing unregulated MAC deposition, exacerbates the renal injury in this model of immune complex-mediated glomerulonephritis.

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Endothelial Cell Activation by Pore-Forming Structures

Abstract: These findings suggest that transmembrane pore-forming proteins, as a class of molecules, activate ECs through the autocrine effects of IL-1alpha.

Cited by 85 publications

References 28 publications

Accommodation: Preventing Injury in Transplantation and Disease

Accommodation: Preventing Injury in Transplantation and Disease

IL-1α and IL-1β Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

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