The terminal complement complex C5b‐9 stimulates interleukin‐6 production in human smooth‐muscle cells through activation of transcription factors NF‐κB and AP‐1

Viedt, Christiane; Hänsch, G M; Brandes, Ralf P.; Kübler, W.; Kreuzer, Jörg

doi:10.1096/fj.00-0468fje

Cited by 86 publications

(57 citation statements)

References 30 publications

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“…MAC-induced activation of synovial cells in vitro has been well described (37,38), although the signaling pathways involved are poorly defined. In several other cell types, NF-B activation has been implicated, and this finding suggests the possibility of a common signaling pathway for MAC activation in tissues (39,40). The nonlytic effects of MAC in vivo are less clear, but MAC-dependent expression of the chemokine IL-8 from synovial cells, with resultant inflammatory cell infiltration, was recently described by investigators using C6-deficient rabbits in the AIA model (35).…”

Section: Discussionmentioning

confidence: 99%

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Williams¹,

Mizuno²,

Richards³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate the roles of CD59a in the protection of joint tissue in the context of murine antigen-induced arthritis (AIA).Methods. AIA was triggered in CD59a-deficient (CD59a ؊/؊ ) mice and in CD59a-sufficient (CD59a ؉/؉ ) controls; the course and severity of disease were compared between groups. The effects on arthritis of restoring CD59 to the joint in CD59a ؊/؊ mice by use of a membrane-targeted recombinant CD59 were also explored.Results. Disease, as assessed clinically by measurement of joint swelling on day 1 (P < 0.0001), day 2 (P < 0.01), and day 7 (P < 0.02) and histologically from indicators of joint damage on day 21 (P < 0.02), was significantly enhanced in CD59a ؊/؊ mice compared with CD59a؉/؉ wild-type controls. Membrane attack complex (MAC) deposition in the arthritic joints of CD59a ؊/؊ mice was also increased compared with that in the joints of CD59a ؉/؉ controls. Restitution of CD59 activity in joints of CD59a ؊/؊ mice was attempted with soluble recombinant rat CD59 (sCD59) or with a novel membrane-targeted rat CD59 derivative (sCD59-APT542). Strong immunohistochemical staining of the synovial membrane and subsynovial tissue was apparent in sCD59-APT542-injected joints, but not in joints injected with untargeted sCD59. Intraarticular administration of sCD59-APT542 markedly ameliorated disease severity in CD59a ؊/؊ mice, knee swelling was significantly reduced over the time course of the disease, and joint damage, assessed histologically, was significantly milder on day 21 (P < 0.05).Conclusion. These data firmly implicate the MAC of complement as a major effector of joint damage in the murine AIA model of rheumatoid arthritis (RA), and they provide a rationale for the inhibition of MAC assembly as a therapeutic strategy for RA.

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Section: Discussionmentioning

confidence: 99%

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Williams¹,

Mizuno²,

Richards³

et al. 2004

Arthritis & Rheumatism

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“…Generation of anti-glycated hCD59 polyclonal antibody. The antigen was a 14-amino acid peptide (hCD59 [37][38][39][40][41][42][43][44][45][46][47][48][49][50] ) synthesized by solid-phase chemistry using an ε-glucitol-lysine residue at the position corresponding to lysine 41 in the native protein. This glycated peptide was conjugated to keyhole limpet hemocyanin and injected into rabbits for immunization as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

Glycation Inactivation of the Complement Regulatory Protein CD59

et al. 2004

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Micro-and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes. Diabetes 53: [2653][2654][2655][2656][2657][2658][2659][2660][2661] 2004

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“…Part of these events is thought to be a consequence of dialyzer-associated activation of the complement system through the alternative pathway (21). Recently, the terminal complement complex C5b-9 was suggested to modulate several cell functions in a variety of cell types (22,23). Thus, at the end of each experimental period, we first evaluated the ability of the different membranes to generate C5b-9 complex.…”

Section: Effect Of Ca and Eval Membranes On C5b-9 Generationmentioning

confidence: 99%

Coagulation Cascade Activation Causes CC Chemokine Receptor-2 Gene Expression and Mononuclear Cell Activation in Hemodialysis Patients

Pertosa

Simone

Soccio

et al. 2005

Journal of the American Society of Nephrology

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Priming of the coagulation cascade during hemodialysis (HD) leads to the release of activated factor X (FXa). The binding of FXa to its specific receptors, effector protease receptor-1 (EPR-1) and protease-activated receptor-2 (PAR-2), may induce the activation of peripheral blood mononuclear cells (PBMC) and promote a chronic inflammatory state that is responsible for several HD-related morbidities. In the attempt to elucidate the mechanisms underlying the coagulation-associated inflammation in HD, 10 HD patients were randomized to be treated subsequently with a cellulose acetate membrane (CA) and Ethylen-vinyl-alcohol (EVAL), a synthetic membrane that has been shown to reduce FXa generation. At the end of each experimental period, surface FXa and thrombin receptors (EPR-1 and PAR-1, -2, and -4) and CCR2 (monocyte chemoattractant protein-1 receptor) gene expression in isolated PBMC were examined. the ability of dialytic membranes to activate proteintyrosine kinases and the stress-activated kinase JNK and to modulate the generation of terminal complement complex (TCC) was also investigated. EPR-1 and PAR-2 and -4 mRNA expression, barely detectable in normal PBMC, were significantly upregulated in HD patients, particularly in those who were treated with CA. A striking increase of tyrosine-phosphorylated proteins and JNK activation was observed at the end of HD only in CA-treated patients. Simultaneously, an increased gene expression for both splicing isoforms of CCR2, A and B, only in PBMC from CA-treated patients was demonstrated. The increased CCR-2 mRNA abundance was followed by a significant increase in its protein synthesis. The high expression of CCR2 was associated with an increased generation of plasma TCC and a significant drop in leukocyte and monocyte count. By contrast, EVAL treatment slightly lowered TCC generation and normalized leukocyte count. In vitro FXa induced CCR2 A and B expression and JNK activation in freshly isolated PBMC. FXa-induced CCR2 mRNA expression was completely abolished by JNK and tyrosine kinase inhibition. In conclusion, these data suggest that subclinical clotting activation may cause an increased CCR2 gene and protein expression on uremic PBMC, contributing to HD-related chronic microinflammation. The use of the less coagulation-activating membrane, EVAL, may reduce PBMC activation through the modulation of the stress-activated kinase JNK.

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The terminal complement complex C5b‐9 stimulates interleukin‐6 production in human smooth‐muscle cells through activation of transcription factors NF‐κB and AP‐1

Cited by 86 publications

References 30 publications

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Glycation Inactivation of the Complement Regulatory Protein CD59

Coagulation Cascade Activation Causes CC Chemokine Receptor-2 Gene Expression and Mononuclear Cell Activation in Hemodialysis Patients

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