Genomes and Genes
Summary: The smaller fragment generated from the cleavage of complement C3 by C3 CONVERTASE. C3a, a 77-amino acid peptide, is a mediator of local inflammatory process. It induces smooth MUSCLE CONTRACTION, and HISTAMINE RELEASE from MAST CELLS and LEUKOCYTES. C3a is considered an anaphylatoxin along with COMPLEMENT C4A; COMPLEMENT C5A; and COMPLEMENT C5A, DES-ARGININE.
- Habermann J, Roblick U, Luke B, Prieto D, Finlay W, Podust V, et al. Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors. Gastroenterology. 2006;131:1020-9; quiz 1284 pubmed..Based on a specific enzyme-linked immunosorbent assay, serum levels of complement C3a-desArg predicted the presence of colorectal malignancy in a blinded validation set (n = 59) with a sensitivity ..
- Barnum S, Ames R, Maycox P, Hadingham S, Meakin J, Harrison D, et al. Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation. Glia. 2002;38:169-73 pubmed..This latter result highlights the importance of including this important control group in ischemic model systems for proper interpretation of changes in gene expression. ..
- Zwirner J, Werfel T, Wilken H, Theile E, Gotze O. Anaphylatoxin C3a but not C3a(desArg) is a chemotaxin for the mouse macrophage cell line J774. Eur J Immunol. 1998;28:1570-7 pubmed..In summary, our findings demonstrate for the first time a specific, receptor-mediated chemoattraction of cells of the monocytic lineage to the anaphylatoxin C3a which may contribute to the accumulation of Mø at sites of inflammation. ..
- Schraufstatter I, DiScipio R, Zhao M, Khaldoyanidi S. C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. J Immunol. 2009;182:3827-36 pubmed publisher..These results suggest that the anaphylatoxins C3a and C5a present in injured tissues contribute to the recruitment of MSCs and regulation of their behavior. ..
- Dillard P, Wetsel R, Drouin S. Complement C3a regulates Muc5ac expression by airway Clara cells independently of Th2 responses. Am J Respir Crit Care Med. 2007;175:1250-8 pubmed..These studies identify a novel C3a receptor-dependent mechanism in the development of airway epithelial goblet cells and regulation of Muc5ac production and implicate C3a as a mediator of airway obstruction in asthma. ..
- Monsinjon T, Gasque P, Ischenko A, Fontaine M. C3A binds to the seven transmembrane anaphylatoxin receptor expressed by epithelial cells and triggers the production of IL-8. FEBS Lett. 2001;487:339-46 pubmed..Pre-treatment of ECV 304 with pertussis toxin inhibited IL-8 response induced by C3a, indicating that the action of C3a was mediated by a G protein coupled pathway. ..
- Sakuma M, Morooka T, Wang Y, Shi C, Croce K, Gao H, et al. The intrinsic complement regulator decay-accelerating factor modulates the biological response to vascular injury. Arterioscler Thromb Vasc Biol. 2010;30:1196-202 pubmed publisher..Targeting the C3a and C5a receptors may be useful for the prevention of neointimal hyperplasia. ..
- Drouin S, Corry D, Hollman T, Kildsgaard J, Wetsel R. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol. 2002;169:5926-33 pubmed
- Mocco J, Wilson D, Komotar R, Sughrue M, Coates K, Sacco R, et al. Alterations in plasma complement levels after human ischemic stroke. Neurosurgery. 2006;59:28-33; discussion 28-33 pubmed..Together, these data confirm complement activation after stroke and suggest that this activation is a heterogeneous process, with varying responses for different components. ..
- Ducruet A, Hassid B, Mack W, Sosunov S, Otten M, Fusco D, et al. C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. J Cereb Blood Flow Metab. 2008;28:1048-58 pubmed publisher..It further establishes antagonism of the C3a anaphylatoxin as a promising strategy for ameliorating injury after ischemia/reperfusion. ..
- Nakano Y, Morita S, Kawamoto A, Suda T, Chida K, Nakamura H. Elevated complement C3a in plasma from patients with severe acute asthma. J Allergy Clin Immunol. 2003;112:525-30 pubmed..7 microg/L; 14.6 to 160; P =.99). Concentrations of C3a, which can induce airway inflammation and bronchoconstriction, were associated with differences in response to emergency treatment of severe asthma exacerbation. ..
- Cui W, Lapointe M, Gauvreau D, Kalant D, Cianflone K. Recombinant C3adesArg/acylation stimulating protein (ASP) is highly bioactive: a critical evaluation of C5L2 binding and 3T3-L1 adipocyte activation. Mol Immunol. 2009;46:3207-17 pubmed publisher..rASP stimulation of adipocyte BODIPY-fatty acid uptake demonstrated EC(50) 115+/-93 nM and maximal stimulation of 413+/-33%, p<0.001. ASP binding has distinct characteristics that lead to C5L2 activation and increased bioactivity. ..
- Peng Q, Li K, Sacks S, Zhou W. The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Allergy Drug Targets. 2009;8:236-46 pubmed..In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses. ..
- Mizutani N, Nabe T, Yoshino S. Complement C3a regulates late asthmatic response and airway hyperresponsiveness in mice. J Immunol. 2009;183:4039-46 pubmed publisher..In this study, we attempted to elucidate the contribution of the complement C3a to these asthmatic symptoms. BALB/c mice sensitized by i.p...
- Peng Q, Li K, Anderson K, Farrar C, Lu B, Smith R, et al. Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction. Blood. 2008;111:2452-61 pubmed..This mechanism, in addition to underpinning the cell-autonomous action of donor C3 on allostimulation, has implications for a wider range of immune responses in self-restricted T-cell priming. ..
- Liu J, Lin F, Strainic M, An F, Miller R, Altuntas C, et al. IFN-gamma and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production. J Immunol. 2008;180:5882-9 pubmed
- Honczarenko M, Ratajczak M, Nicholson Weller A, Silberstein L. Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor. J Immunol. 2005;175:3698-706 pubmedb>Complement C3a promotes CXCL12-induced migration and engraftment of human and murine hemopoietic progenitor cells, suggesting a cross-influence between anaphylatoxin and chemokine axes...
- Gutzmer R, Lisewski M, Zwirner J, Mommert S, Diesel C, Wittmann M, et al. Human monocyte-derived dendritic cells are chemoattracted to C3a after up-regulation of the C3a receptor with interferons. Immunology. 2004;111:435-43 pubmed..Therefore, dendritic cells represent another group of target cells that might be recruited by C3a to areas of inflammation, in particular under conditions where IFNs are increased in the surrounding environment. ..
- Murray I, Sniderman A, Cianflone K. Mice lacking acylation stimulating protein (ASP) have delayed postprandial triglyceride clearance. J Lipid Res. 1999;40:1671-6 pubmed..The data are consistent therefore, with the hypothesis that the ASP pathway is an important physiologic determinant of normal postprandial triglyceride clearance. ..
- Monsinjon T, Gasque P, Chan P, Ischenko A, Brady J, Fontaine M. Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. FASEB J. 2003;17:1003-14 pubmed..Finally, we showed that C3a and C5a both strongly activate downstream MAP kinase signaling pathways (p44 and p42 Erk kinases). ..
- Kalant D, Cain S, Maslowska M, Sniderman A, Cianflone K, Monk P. The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. J Biol Chem. 2003;278:11123-9 pubmed..Thus C5L2, a promiscuous complement fragment-binding protein with a high affinity site that binds C3a des-Arg(77)/ASP, may mediate the acylation-stimulating properties of this peptide. ..
- Schraufstatter I, Trieu K, Sikora L, Sriramarao P, DiScipio R. Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol. 2002;169:2102-10 pubmed..The C5aR in endothelial cells thus uses a signaling cascade-transactivation of the EGFR-that does not exist in leukocytes, while the C3aR couples to a different G protein, presumably G(alpha12/13). ..
- Scully C, Blakeney J, Singh R, Hoang H, Abbenante G, Reid R, et al. Selective hexapeptide agonists and antagonists for human complement C3a receptor. J Med Chem. 2010;53:4938-48 pubmed publisher..Derivatization produced a noncompetitive and insurmountable antagonist of C3aR. Small molecule C3a agonists and antagonists may be valuable probes of immunity and inflammatory diseases. ..
- Stokowska A, Olsson S, Holmegaard L, Jood K, Blomstrand C, Jern C, et al. Plasma C3 and C3a levels in cryptogenic and large-vessel disease stroke: associations with outcome. Cerebrovasc Dis. 2011;32:114-22 pubmed publisher..Further studies on the role of the complement system in ischemic stroke outcome based on larger patient populations and controlling for the effect of infections, are clearly warranted. ..
- Kirchhoff K, Weinmann O, Zwirner J, Begemann G, Gotze O, Kapp A, et al. Detection of anaphylatoxin receptors on CD83+ dendritic cells derived from human skin. Immunology. 2001;103:210-7 pubmed..Furthermore, the expression of anaphylatoxin receptors on CD83+ dermal DC is indicative of an intermediate stage of maturation of these cells, which was not observed on in vitro-differentiated CD83+ cells. ..
- Li K, Anderson K, Peng Q, Noble A, Lu B, Kelly A, et al. Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood. 2008;112:5084-94 pubmed publisher..The finding of a link between complement and adaptive immune stimulation through cAMP offers new insight into how innate and adaptive immunity combine to generate efficient effector and memory responses. ..
- Humbles A, Lu B, Nilsson C, Lilly C, Israel E, Fujiwara Y, et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature. 2000;406:998-1001 pubmed..We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma. ..
- Haas P, van Strijp J. Anaphylatoxins: their role in bacterial infection and inflammation. Immunol Res. 2007;37:161-75 pubmed
- Fan Y, Wang J, Yang Y, Liu Q, Fan Y, Yu J, et al. Detection and identification of potential biomarkers of breast cancer. J Cancer Res Clin Oncol. 2010;136:1243-54 pubmed publisher..An efficient strategy, including SELDI-TOF-MS analysis, HPLC purification, MALDI-TOF-MS trace and LC-MS/MS identification, has been proved very successful. ..
- Chen N, Mirtsos C, Suh D, Lu Y, Lin W, McKerlie C, et al. C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature. 2007;446:203-7 pubmed..Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses. ..
- Francis K, Lewis B, Akatsu H, Monk P, Cain S, Scanlon M, et al. Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation. FASEB J. 2003;17:2266-8 pubmed..We propose that the complement innate immune molecules (cytokines) modulate tissue-specific and systemic inflammatory responses through communication with the endocrine pituitary gland. ..
- Maslowska M, Legakis H, Assadi F, Cianflone K. Targeting the signaling pathway of acylation stimulating protein. J Lipid Res. 2006;47:643-52 pubmed..ASP signaling involves sequential activation of PI3K and PLC, with downstream activation of protein kinase C, Akt, MAPK/ERK(1/2), and cPLA(2), all of which leads to an effective and prolonged stimulation of TGS. ..
- Strey C, Markiewski M, Mastellos D, Tudoran R, Spruce L, Greenbaum L, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198:913-23 pubmed..These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration. ..
- Kashem S, Subramanian H, Collington S, Magotti P, Lambris J, Ali H. G protein coupled receptor specificity for C3a and compound 48/80-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. Eur J Pharmacol. 2011;668:299-304 pubmed publisher..It further reveals the novel finding that the previously characterized synthetic peptide, C3a receptor "superagonist" E7 activates human mast cells via two mechanisms; one involving the C3a receptor and the other MrgX2. ..
- Cianflone K, Zakarian R, Couillard C, Delplanque B, Despres J, Sniderman A. Fasting acylation-stimulating protein is predictive of postprandial triglyceride clearance. J Lipid Res. 2004;45:124-31 pubmed..Plasma ASP may be useful as a fasting variable that will provide additional information regarding ppTG and NEFA clearance. ..
- Cui W, Simaan M, Laporte S, Lodge R, Cianflone K. C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation. Mol Immunol. 2009;46:3086-98 pubmed publisher..C5L2 is a functional metabolic receptor, and serine 323 is important for ASP induced functionality. ..
- Saleh J, Summers L, Cianflone K, Fielding B, Sniderman A, Frayn K. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. J Lipid Res. 1998;39:884-91 pubmed
- Guo Q, Subramanian H, Gupta K, Ali H. Regulation of C3a receptor signaling in human mast cells by G protein coupled receptor kinases. PLoS ONE. 2011;6:e22559 pubmed publisher..These findings thus reveal a new level of complexity for C3aR regulation by GRKs in human mast cells. ..
- Rahpeymai Y, Hietala M, Wilhelmsson U, Fotheringham A, Davies I, Nilsson A, et al. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006;25:1364-74 pubmed..Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis. ..
- Fineschi V, Riezzo I, Cantatore S, Pomara C, Turillazzi E, Neri M. Complement C3a expression and tryptase degranulation as promising histopathological tests for diagnosing fatal amniotic fluid embolism. Virchows Arch. 2009;454:283-90 pubmed publisher..In all studied cases, expression of complement C(3a) was twofold lower than in the control group, suggesting a possible complement activation in AFE, initiated by fetal antigen leaking into the maternal circulation. ..
- Nozaki M, Raisler B, Sakurai E, Sarma J, Barnum S, Lambris J, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103:2328-33 pubmed..Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD...
- Kawamoto S, Yalcindag A, Laouini D, Brodeur S, Bryce P, Lu B, et al. The anaphylatoxin C3a downregulates the Th2 response to epicutaneously introduced antigen. J Clin Invest. 2004;114:399-407 pubmed..These results suggest that C3a-C3aR interactions inhibit the ability of APCs to drive Th2 cell differentiation in response to epicutaneously introduced antigen and may have important implications for allergic skin diseases. ..
- Campbell W, Lazoura E, Okada N, Okada H. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol. 2002;46:131-4 pubmed
- Krug N, Tschernig T, Erpenbeck V, Hohlfeld J, Kohl J. Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med. 2001;164:1841-3 pubmed..However, the pathogenic role of these substances in relation to asthma remains to be elucidated, for example, by using anaphylatoxin receptor blockers as a possible new therapeutic principle. ..
- Markiewski M, DeAngelis R, Strey C, Foukas P, Gerard C, Gerard N, et al. The regulation of liver cell survival by complement. J Immunol. 2009;182:5412-8 pubmed publisher..In conclusion, this study documents functions of complement proteins as prosurvival factors that, through their interactions with cytokines, inhibit apoptotic signaling in proliferating cells of epithelial origin. ..
- Bogestål Y, Barnum S, Smith P, Mattisson V, Pekny M, Pekna M. Signaling through C5aR is not involved in basal neurogenesis. J Neurosci Res. 2007;85:2892-7 pubmed..Our results indicate that signaling through C5aR is not involved in basal neurogenesis in adult mice and that basal neurogenesis in adult C3a/GFAP and C5a/GFAP mice is not altered. ..
- Erdei A, Andrásfalvy M, Péterfy H, Toth G, Pecht I. Regulation of mast cell activation by complement-derived peptides. Immunol Lett. 2004;92:39-42 pubmed..Based on the current results we propose the presence of separate "activator" and "inhibitor" sequence motifs in C3a which are in balance under physiologic conditions. ..
- Murray I, Havel P, Sniderman A, Cianflone K. Reduced body weight, adipose tissue, and leptin levels despite increased energy intake in female mice lacking acylation-stimulating protein. Endocrinology. 2000;141:1041-9 pubmed..Thus, ASP appears to have an important role in the regulation of energy balance in mice. ..
- Bera M, Lu B, Martin T, Cui S, Rhein L, Gerard C, et al. Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. J Immunol. 2011;187:4245-55 pubmed publisher..Deficiency of either receptor affords protection from AHR, identifying two potential therapeutic targets. ..
- Strainic M, Shevach E, An F, Lin F, Medof M. Absence of signaling into CD4? cells via C3aR and C5aR enables autoinductive TGF-?1 signaling and induction of Foxp3? regulatory T cells. Nat Immunol. 2013;14:162-71 pubmed publisher..The resulting iT(reg) cells exerted robust suppression, had enhanced stability and suppressed ongoing autoimmune disease. Antagonism of C3aR and C5aR can also induce functional human iT(reg) cells. ..
- van Beek J, Nicole O, Ali C, Ischenko A, MacKenzie E, Buisson A, et al. Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death. Neuroreport. 2001;12:289-93 pubmed..These observations suggest that C3a is involved in excitotoxicity-mediated neuronal death through astrocyte stimulation and extend its role beyond immune functions. ..
- Drouin S, Kildsgaard J, Haviland J, Zabner J, Jia H, McCray P, et al. Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. J Immunol. 2001;166:2025-32 pubmed
- Bautsch W, Hoymann H, Zhang Q, Meier Wiedenbach I, Raschke U, Ames R, et al. Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma. J Immunol. 2000;165:5401-5 pubmed..These data suggest an important role of C3a in the pathogenesis of asthma and define a novel target for drug intervention strategies. ..