Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells

Schieferdecker, Henrike L.; Schlaf, Gerald; Jungermann, Kurt; Götze, Otto

doi:10.1016/s1567-5769(00)00038-2

Cited by 77 publications

(52 citation statements)

References 69 publications

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“…C3a and C5a stimulate the production of cytokines in a number of cell types (35;39), either alone or in the presence of other inflammatory mediators, such as LPS (39). C5a is generally much more pro-inflammatory than C3a with respect to effects on blood flow, lymphatic drainage and vascular permeability and neutrophil activation, and consequently, with respect to local concentrations of agonists and complement components (21).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their role in the formation of the membrane attack complex, the complement cleavage products C3a, C3b and C5a, resulting from the activation of C3, together contribute to a number of pro-inflammatory and protective responses, including phagocyte recruitment, opsonization of pathogens and lysis of certain pathogens and cells. The C3a-and C5a-mediated responses are characterized by the stimulation of cytokine production (35;39), either alone or in the presence of other inflammatory mediators, such as lipopolysaccharide (LPS) (39), as well as increased expression of chemokines and adhesion molecules (11;23).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

et al. 2007

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“…C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. [2][3][4] Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.…”

Section: Introductionmentioning

confidence: 99%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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Plasma procarboxypeptidase B (proCPB)is activated by the endothelial thrombinprothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPBdeficient mice (proCPB ؊/؊ ). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB ؊/؊ mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB ؊/؊ mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. IntroductionThe complement system is part of the innate immune system and plays a major role in the host defense against pyrogenic bacterial infection. 1,2 It is also involved in a wide variety of acute and chronic inflammatory disorders, including sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and glomerulonephritis. The complement system consists of multiple proteins in plasma and on cell surfaces and can be activated by 3 distinct pathways, all converging on the cleavage of C3 into C3a and C3b. C3b in turn becomes an essential component of the C5 convertase enzyme complex, leading to cleavage of C5 into C5a and C5b. Both C3a and C5a are strong chemoattractants. 1,2 They cause oxidative burst and enhance phagocytosis and granule enzyme release in neutrophils. They are vasodilators at sites of inflammation. C3a and C5a exert their effects through binding to cellular C3a receptors (C3aR) and C5a receptors (C5aR), respectively. C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. 2-4 Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.Thrombin-activatable procarboxypeptidase B (proCPB), also known as procarboxypeptidase U, procarboxypeptidase R, and thrombin-activatable fibrinolysis inhib...

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“…18,19 C5a exerts its effects through the high-affinity receptors, mainly CD88 (C5aR). C5aR expression was not only described on myeloid cells, including neutrophils and macrophages, but also found on a variety of nonmyeloid cells in many organs, [20][21][22] which suggests the implication of C5a/C5aR signaling in the pathogenesis of organ-specific inflammation.…”

mentioning

confidence: 99%

Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

Chen¹,

Yang

Gao

et al. 2011

Laboratory Investigation

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Complement represents a chief component of innate immunity in host defense. However, excessive complement activation has been involved in the pathogenesis of inflammatory diseases. In this study, we investigated the contribution of complement to intestinal pathology of patients and rodents with inflammatory bowel disease. The expression of complement effectors (C3a and C3) was increased remarkably in inflamed colons of IBD patients compared with those of normal counterparts. In accordance with this, the sustained activation of complement in serum and colon (including elevated C3a and C5a levels, enhanced hemolytic activity, downregulated expression of C5a receptors) was observed, following the establishment of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which peaked at 24 h. Mice pretreated with neutralizing anti-C5a antibodies (À2, 0, and 2 days after TNBS instillation) had significantly reduced weight loss and improved macroscopic/microscopic scores, comparable to the efficacy of prednisolone treatment. Strikingly, treatment with anti-C5a at 24 h after TNBS instillation showed remarkable therapeutic effects, whereas prednisolone did not. The efficacy of anti-C5a administration was associated with decreased release of proinflammatory chemokines and cytokines, inhibition of infiltration of neutrophils into colons, and enhanced Th2 response. These findings suggest a disease-promoting role of complement, particular C5a, in the pathology of TNBS-induced colitis in mice, indicating possible therapeutic potentials for C5a-specific antibody in IBD. The inflammatory bowel diseases (IBDs) encompassing Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of gastrointestinal tract, characterized by dysfunction of mucosal T cells, abnormal cytokine production, cellular inflammation, and ultimately damage to the intestinal lining. 1 Although the etiology of IBD remains unknown, there is circumstantial evidence to link IBD to the mucosal immune system's failure to attenuate immunity to endogenous antigen. 1 In recent years, several animal IBD models have been developed. 2,3 Although the relationship of many of these models to human disease is imperfect, the hapten-induced model of colonic inflammation in which 2,4,6-trinitrobenzene sulfonic acid (TNBS) is delivered intrarectally to BALB/c mice displays human CD-like features, notably predominantly IL-12-driving Th1 activity of the mucosal CD4 þ T-cell population and transmural mononuclear inflammation. 3 More recently, a pathogenic role of IL-23, the cytokine sharing p40 subunits with IL-12, has been evidenced in the development of CD. 4 Deficiency of IL-23-specific subunits (p19) leads to failure of colitis induction in a T-cell transfer model. This effect is attributed to suppression of IL-17 production and Th17 differentiation in the colons. 5 The factors that initiate intestinal pathology of CD and elicit Th1/Th17 immune reaction, however, are still

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Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells

Cited by 77 publications

References 69 publications

Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

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