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At least 19 recordsLinked to original sources
PubMed2005

Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor.

Complement C3a promotes CXCL12-induced migration and engraftment of human and murine hemopoietic progenitor cells, suggesting a cross-influence between anaphylatoxin and chemokine axes. Here we have explored the underlying mechanism(s) of complement anaphylatoxin and chemokine cooperation. In addition to C3a, C3a-desArg and C4a but not C5a, are potent enhancers of CXCL12-induced chemotaxis of human and murine bone marrow (BM) stem/progenitor cells and B lineage cells. C3a enhancement of chemotaxis is chemokine specific because it is also observed for chemotaxis to CCL19 but not to CXCL13. The potentiating effect of C3a on CXCL12 is independent of the classical C3a receptor (C3aR). First, human BM CD34(+) and B lineage cells do not express C3aR by flow cytometry. Second, the competitive C3aR inhibitor SB290157 does not affect C3a-mediated enhancement of CXCL12-induced chemotaxis. Third, enhancement of chemotaxis of hemopoietic cells is also mediated by C3a-desArg, which does not bind to C3aR. Finally, C3a enhances CXCL12-induced chemotaxis of BM cells from C3aR knockout mice similar to BM cells from wild-type mice. Subsequent studies revealed that C3a increased the binding affinity of CXCL12 to human CXCR4(+)/C3aR(-), REH pro-B cells, which is compatible with a direct interaction between C3a and CXCL12. BM stromal cells were able to generate C3a, C3a-desArg, C4a, as well as CXCL12, suggesting that this pathway could function in vivo. Taken together, we demonstrate a C3a-CXCL12 interaction independent of the C3aR, which may provide a mechanism to modulate the function of CXCL12 in the BM microenvironment.

Anaphylatoxins↗
PubMed1990

A screening test for modified hemoglobin blood substitutes before clinical use: based on C3a complement activation in human plasma.

Modified hemoglobin preparations may potentially cause hypersensitivity and anaphylactic reactions, antibody-antigen reactions and other problems. Unfortunately response in animal safety studies may not reflect the same response in human. The next best test before clinical trial in human may the use of human plasma in-vitro. This paper present an in-vitro procedure based on complement activation (C3a) of human plasma. The procedure involves collecting heparinised blood and separating the plasma and freezing the heparinised plasma at -70 degrees C until use. Each 100 lambda of control or test samples is added to 400 lambda of this plasma. This is incubated at 37 degrees C, 60 rpm for 1 hour, then added to EDTA saline to stop the reaction and stored at -70 degrees C until analysed by standard radioimmunoassay for C3a. (C3 measurement is not sensitivity enough). Using the screening test procedure described above, C3a levels (ng/ml) in plasma were: control, 1,980 +/- 280; Zymosan, 20,000; Hemoglobin preparation A, 2,227 +/- 617; Hemoglobin preparation B, 4,967 +/- 153; A 75% + B 25%, 3,967 +/- 270; A 50% + B 50%, 4,553 +/- 517; A 25% + B 75%, 4,920 +/- 430. Hemoglobin preparation A did not cause significant increases in C3a complement activation. Hemoglobin preparation B caused significant increase in C3a complement activation. Serial dilution of Hemoglobin preparation B in Hemoglobin preparation A continued to cause the same degree of C3a complement activation. This is not due to C3 exhaustion because Zymosan resulted in C3a of greater than 20,000ng/ml. This appears to show that this screening test can detect complement activation even at low concentrations of the hemoglobin preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Substitutes↗
PubMed2000

Anti-analgesic and anti-amnesic effect of complement C3a.

In the present study, we found that complement C3a exerted central effects after intracerebroventricular administration in mice. At doses of 3 and 10 pmol/mouse, the peptide showed an antagonistic effect on analgesia induced by morphine and U-50488H, known to be mu- and kappa-opioid receptor agonists, respectively. Moreover, complement C3a improved scopolamine- and ischemia-induced amnesia at a dose of 10 pmol/mouse. Anti-analgesia was not observed by C3a des-Arg at 10 pmol/mouse. The present findings suggest that complement C3a may act as a peptide with anti-opioid activity in the central nervous system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Cloning, expression, sequence determination, and chromosome localization of the mouse complement C3a anaphylatoxin receptor gene.

The complement C3a anaphylatoxin receptor (C3aR) is a seven-transmembrane G-protein coupled chemoattractant receptor that on binding the C3a peptide ligand mediates numerous cellular responses, including histamine release from mast cells. smooth muscle contraction, and the directed migration of eosinophils. To delineate the murine C3aR coding sequence, gene structure, 5'-flanking region, and chromosome location, cDNA and genomic clones encoding the mouse C3a receptor were isolated, characterized, and used in fluorescence in situ hybridization experiments. The results from this study indicate that the murine C3a receptor structural gene is a single copy gene of approximately 8 kb comprised of 2 exons which are separated by a large intervening intron of 4724 bp. The first exon encodes 97 bp of 5'-untranslated sequence. Exon 2 encodes the remaining 8 bp of 5'-untranslated sequence and the entire coding and 3'-untranslated sequences. This genomic organization is typical of most other chemoattractant receptor genes in that the entire coding sequence is contained on a single exon. The human and mouse C3a receptor genes were localized to syntenic chromosomal bands 12q13.2-3 and 6F1, respectively. No other seven-transmembrane receptor genes, to date, have been localized to these chromosomal regions. Primer extension experiments using mouse macrophage RNA indicated a single transcriptional initiation site. Sequence analysis 5' of the transcriptional site indicated a TATA-less promoter with possible cis-acting motifs that may regulate C3a receptor gene expression. These included the recognition sequence for the nuclear transcription factor SP1 and the phorbol ester response sequence which binds the Fos/Jun heteromeric transcription factor AP1.

Amino Acid Sequence↗
PubMed1989

[Effects of nicotine and cigarette smoke extracts on plasma level of complement C3a and C5a, thromboxane B2 and 6-keto PGF1 alpha in rabbits].

In the present investigation we measured plasma levels of complement C3a and C5a, thromboxane B2 (TxB2) and 6-keto PGF1 alpha in anesthetized rabbits by radioimmunoassay after the intravenous injection of nicotine and cigarette smoke extracts. Plasma levels of complement C3a in rabbits showed a significant increased and reached a maximum value 60 minutes after the intravenous injection of nicotine and cigarette smoke extract. Plasma levels of complement C5a in rabbits showed a significant increase and reached a maximum value 30 minutes after the intravenous injection of nicotine. Plasma levels of complement C5a in rabbits showed a significant increase and reached a maximum value 60 minutes after the intravenous injection of cigarette smoke extract. Plasma levels of TxB2 in rabbits showed a significant increase after the intravenous injection of nicotine and cigarette smoke extract. Plasma levels of 6-keto PGF1 alpha in rabbits did not show any change after the intravenous injection of nicotine and cigarette smoke extracts. The above results may suggest that the intravenous injection of nicotine and cigarette smoke extracts induces an increase of plasma levels of complement C3a and C5a and TxB2 in anesthetized rabbits.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Effects of cigarette smoking on blood levels of leukotrienes and plasma levels of complements C3a and C5a in healthy volunteers.

We reported previously that cigarette smoking induces bronchoconstriction. In the present investigation we measured the level of peripheral venous blood leukotrienes, which are known to cause marked bronchoconstriction, and plasma complement C3a and C5a, which are known to have chemotactic and anaphylatoxic activities. All of these showed a significant increase after cigarette smoking. These data may suggest that the activation of complement induces the release of leukotrienes, and that these leukotrienes cause bronchoconstriction. It appears likely, therefore, that cigarette smoking induces an increase in peripheral venous blood leukotrienes and complement C3a and C5a, and that such an increase may elicit bronchoconstriction.

Adult↗
PubMed2006

Identification of complement C3a as a candidate biomarker in human chronic hepatitis C and HCV-related hepatocellular carcinoma using a proteomics approach.

Although the significant risk factors for hepatocellular carcinoma (HCC) are well known from epidemiological studies, diagnosis of this disease at an early stage is difficult, and HCC remains one of the leading causes of cancer death worldwide. Thus, to identify any useful HCC-related biomarkers is still a need. We performed SELDI-TOF MS to identify differentially expressed proteins in HCC serum using weak cation exchange protein chips. Protein characterization was performed by 2-DE separation and nano flow LC-MS/MS. A total of 55 sera were collected from HCC patients and compared with those from 48 patients with chronic hepatitis and 9 healthy individuals. A candidate marker of about 8900 Da was detected as differentially expressed in patients with chronic hepatitis C and hepatitis C virus (HCV)-related HCC. We identified this differentially expressed protein as complement C3a. The expression of C3a in HCC sera was further validated by PS20 chip immunoassay and Western blotting. Complement C3a was found to be elevated in patients with chronic hepatitis C and HCV-related HCC. The combination of SELDI-TOF MS and 2-DE provides a solution to identify disease-associated serum biomarkers.

Aged↗
PubMed2003

Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation.

Two-way communication exists between the endocrine and immune systems using molecules such as hormones and cytokines. Here we describe a new pathway by which C3a, a complement-derived cytokine, stimulates anterior pituitary hormone release and activates the hypothalamic-pituitary-adrenal axis, a reflex central to the stress response and to the control of inflammation. We show that C3a receptors are expressed in pituitary hormone secreting and non-hormone secreting (folliculostellate) cells and that both C3a and C3adesArg (a non-inflammatory metabolite) stimulate pituitary cell cultures to release prolactin, growth hormone, and adrenocorticotropin. Serum levels of these hormones, together with adrenal corticosterone, increase dose dependently with recombinant C3a and C3adesArg administration in vivo. Pertussis toxin blocks the response to C3a but not C3adesArg, which indicates the presence of two receptors, only one of which is coupled to Galphai-proteins. We propose that the complement innate immune molecules (cytokines) modulate tissue-specific and systemic inflammatory responses through communication with the endocrine pituitary gland.

Animals↗
PubMed2007

Suppression of food intake by a complement C3a agonist [Trp5]-oryzatensin(5-9).

[Trp5]-oryzatensin(5-9) (WPLPR), an agonist peptide for complement C3a receptor, has been designed based on the C-terminal region of ileum-contracting peptide oryzatensin derived from rice protein. We previously reported that WPLPR has anti-analgesic and anti-amnesic activities after central or oral administration. In this study, we found a novel function of WPLPR on food intake. WPLPR suppressed food intake after intracerebroventricular or intraperitoneal (i.p.) administration at a dose of 3-30 nmol/mouse or 30-300 mg/kg, respectively, in fasted mice. Orally administered WPLPR at a dose of 300 mg/kg also decreased food intake. WPLPR decreased gastric emptying after i.p. injection at a dose of 300 mg/kg. The anorexigenic activity of WPLPR was blocked by cyclooxygenase inhibitor or antagonist for prostaglandin (PG) E receptor EP4 subtype. These results suggest that WPLPR decreases food intake through PGE2 production followed by EP4 receptor activation.

Amino Acid Sequence↗
PubMed1996

Studies on the ileum-contracting mechanisms and identification as a complement C3a receptor agonist of oryzatensin, a bioactive peptide derived from rice albumin.

Oryzatensin (Gly-Tyr-Pro-Met-Tyr-Pro-Leu-Pro-Arg) is an ileum-contracting and immunostimulating peptide derived from rice albumin. The mechanisms for the ileal contraction that it induces, consisting of rapid and slow components, were examined. The rapid contraction was mediated by histamine release and the slow contraction by a prostaglandin E2-like substance, judging from the effects of various pharmacological inhibitors and antagonists on ileal contraction and titration of histamine release. The contractile profile was very similar to that of human complement C3a(70-77), which is the COOH-terminal octapeptide of C3a and has, although less potent, qualitatively the same biological activities as C3a. Oryzatensin showed homology with C3a(70-77) and affinity for C3a receptors (IC50 = 44 microM) by radioreceptor assay. This is the first report of a food-derived bioactive peptide acting through complement C3a receptors.

Amino Acid Sequence↗
PubMed2001

Designing of an orally active complement C3a agonist peptide with anti-analgesic and anti-amnesic activity.

Complement C3a is an anti-opioid peptide, having anti-analgesic and anti-amnesic effects after intracerebroventricular administration. However, the peptide is inactive after oral administration. Orally active C3a agonist peptide was designed based on the structure of oryzatensin, a C3a agonist peptide derived from rice albumin. Tyr-Pro-Leu-Pro-Arg, a pentapeptide at the carboxyl terminus of oryzatensin is the minimally essential structure for exerting C3a activity. Due to the affinity for mu-opioid receptor, both oryzatensin and Tyr-Pro-Leu-Pro-Arg showed analgesia after intracerebroventricular administration in mice which was blocked by the opioid antagonist naloxone. Tyr-Pro-Leu-Pro-Arg lost opioid activity by substitution the amino terminus tyrosine with other hydrophobic residues. Among the newly designed peptides, Trp-Pro-Leu-Pro-Arg was found to possess the strongest C3a activity. The peptide antagonized morphine-induced analgesia at 300 mg/kg after oral administration and also improved scopolamine- and ischemia-induced amnesia in a step-through passive avoidance test.

Administration, Oral↗
PubMed1990

Interleukin 3 and granulocyte/macrophage-colony-stimulating factor render human basophils responsive to low concentrations of complement component C3a.

Complement component C3a is an anaphylatoxin known to induce plasma exudation and smooth muscle contraction in tissues. The effects on inflammatory effector leukocytes, however, are poorly defined and controversial, being at best weak and occurring at very high C3a concentrations. Here, we examined the effect of C3a upon mediator release from human basophils, with and without pretreatment with interleukin 3 (IL-3), a hematopoietic growth factor recently found to profoundly modify the basophil response to various cell agonists. In the absence of cytokines, C3a, even at a concentration of 1 microM, was ineffective or only weakly stimulatory for basophil mediator release. However, when basophils were pretreated with IL-3 at concentrations of only 0.01-1 unit/ml, they became responsive to C3a, releasing large amounts of histamine and also generating leukotrienes. Surprisingly, almost optimal effects occurred with even very low C3a concentrations (1 nM). Another hematopoietic growth factor, granulocyte/macrophage-colony-stimulating factor (GM-CSF), was also found to render basophils capable of responding to C3a, but the effect was weaker than that of IL-3. C3a-induced histamine release and leukotriene generation occurred rapidly in IL-3-primed cells, being complete after 0.5 and 2 min, respectively. The rapid and strong degranulation response, occurring at very low concentrations of C3a, suggests the presence of a high-affinity C3a receptor on basophils, which might be inducible by cytokines. Our results demonstrate that, depending on the presence of IL-3 or GM-CSF, C3a is a potent basophil activator, and such a phenomenon could be of relevance in various inflammatory processes, especially hypersensitivity reactions.

Basophils↗
PubMed2001

Introduction of a low molecular weight agonist peptide for complement C3a receptor into soybean proglycinin A1aB1b subunit by site-directed mutagenesis.

LPLPR, a complement C3a agonist peptide, with hypocholesterolemic activity was introduced into the homologous site of soybean proglycinin A1aB1b subunit by site-directed mutagenesis. This modified proglycinin was expressed in E. coli and recovered from the insoluble fraction. LPLPR was released by the action of chymotrypsin and trypsin as expected. Furthermore, two peptides (RPSYLPLPR and PSYLPLPR) with extended sequence at the amino-terminus of LPLPR were obtained. Their ileum-contracting activity was 9 to approximately 13 times stronger than that of LPLPR. The overall yields of purified LPLPR, RPSYLPLPR and PSYLPLPR were 25%, 12%, and 0.7% respectively.

Amino Acid Sequence↗
PubMed1992

ELISA of complement C3a in bronchoalveolar lavage fluid.

Activated complement factors within the lung may induce several local biological effects. In order to investigate local complement activation we have developed non-competitive two-site ELISAs of C3a and total C3 in bronchoalveolar lavage fluid (BALF). For the assay of C3a, both C3 and C3(H2O) were removed from the samples by precipitation with polyethylene glycol. It was necessary to add carrier proteins to BALF to remove C3 and C3(H2O) fully. The ELISA of C3a has the lowest limit of detection reported thus far, namely 0.045 nM (= 0.405 ng/ml). In BALF from healthy persons (n = 9) the C3a concentration was 0.20 nM (0.12-0.31 nM) (median, range). C3a was higher in BALF from patients with asthma or with sarcoidosis; asthma (n = 10), 0.45 nM (0.20-5.79 nM); sarcoidosis (n = 19), 1.31 nM (0.095-5.65 nM) (Mann-Whitney U test, p less than 0.005). In BALF from patients with Pneumocystis carinii pneumonitis (n = 10) the C3a concentration was 0.18 nM (0.07-0.57 nM). C3a concentrations in BALF may reflect local complement activation in the lung and/or diffusion into the lumen. This was studied by normalizing C3a concentrations in BALF into values for epithelial lining fluid (ELF), and calculating serum-to-ELF quotients of C3a, and C3a/total C3 quotients.

Adolescent↗
PubMed2002

Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation.

The receptors for the complement anaphylatoxins C3a and C5a are expressed by glial cells and neurons in normal and inflamed brain. Previous studies demonstrated modest elevations in mRNA expression of these receptors in a model of focal cerebral ischemia. Using a similar model system for both mice and rats, we report markedly different patterns of anaphylatoxin receptor mRNA expression in cerebral ischemia. C5a receptor expression was dramatically elevated within 3 h after middle cerebral artery occlusion, while C3aR expression was reduced to 25% of control animals. By 24 h post-occlusion, expression of both receptors was higher than at any other time point examined. This increased expression at late time points after occlusion is most likely the result of massive infiltration of leukocytes expressing the receptors. We also observed increased receptor mRNA expression in sham-operated animals, indicating that the procedures used for arterial occlusion affects mechanisms regulating receptor expression. This latter result highlights the importance of including this important control group in ischemic model systems for proper interpretation of changes in gene expression.

Animals↗
PubMed2002

Albutensin A and complement C3a decrease food intake in mice.

Albutensin A (Ala-Phe-Lys-Ala-Trp-Ala-Val-Ala-Arg) derived from serum albumin dose-dependently decreased food intake after intracerebroventricular (10-50 nmol/mouse) or peripheral (0.3-1.0 micromol/mouse) administration in fasted conscious ddY mice. Albutensin A delayed gastric emptying and elevated blood glucose levels. Although albutensin A showed low affinity for bombesin receptor, it decreased food intake in bombesin receptor knockout mice, indicating that its inhibitory effect on feeding was not mediated through bombesin receptor. Then, we investigated whether the albutensin A-induced decrease in food intake was mediated by complement C3a and C5a receptors, because albutensin A had affinities for these receptors. Des-Arg-albutensin A, lacking affinity for C3a and C5a receptors, did not inhibit food intake. We found for the first time that centrally administered C3a (10-100 pmol/mouse) by itself decreased food intake in fasted mice. In contrast, C5a increased food intake after central injection. Based on these results, we conclude that the inhibitory effect of albutensin A on food intake is mediated through the C3a receptor.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Mechanisms of C5a and C3a complement fragment-induced [Ca2+]i signaling in mouse microglia.

Microglial cells are activated in response to brain insults; the mechanisms of this process are not yet understood. One of the important signaling mechanisms that might be involved in microglia activation is related to changes in the intracellular calcium concentration ([Ca2+]i). Using fluo-3 microfluorimetry, we have found that external application of the complement fragment C5a (4-10 nM) induced [Ca2+]i elevation in microglial cells in situ in corpus callosum slices. Similarly, application of complement fragments C5a (0.1-10.0 nM) or C3a (100 nM) generates biphasic [Ca2+]i transients composed of an initial peak followed by a plateau in cultured microglia. Incubation of microglial cells for 30 min with pertussis toxin (PTX; 1 microgram/ml) inhibited both C5a- and C3a-triggered [Ca2+]i responses, suggesting the involvement of PTX-sensitive G-proteins in the signal transduction chain. Removal of Ca2+ ions from the extracellular solution eliminated the plateau phase and limited the response to the initial peak. The restoration of the extracellular Ca2+ concentration within 30-60 sec after the beginning of the complement fragment-induced [Ca2+]i elevation led to the recovery of the plateau phase. Inhibition of the endoplasmic reticulum Ca2+ pumps with 500 nM thapsigargin transiently increased the [Ca2+]i and blocked the [Ca2+]i signals in response to subsequent complement fragment application. Our data suggest that complement factors induce [Ca2+]i responses by Ca2+ release from internal pools and subsequent activation of Ca2+ entry controlled by the filling state of the intracellular Ca2+ depots.

Animals↗