Characterization of Complement Anaphylatoxins and Their Biological Responses

Ember, Julia A.; Jagels, Mark A.; Hugli, Tony E.

doi:10.1201/b14212-12

Cited by 110 publications

(111 citation statements)

References 150 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…For example, the anaphylatoxins, C3a and C5a, can cause endothelial activation and increased expression of adhesion molecules leading to leukocyte chemotaxis (29). These factors may also lead to smooth muscle cell and vascular constriction, decreasing renal blood flow.…”

Section: Discussionmentioning

confidence: 99%

“…The MAC can directly cause cellular damage, and mice that are deficient in MAC components (C5 and C6) have also been shown to be protected from renal I/R injury (11). Complement activation can also induce endothelial and epithelial cells to elaborate inflammatory cytokines such as IL-1 (29). The relation of complement activation to other known or postulated mediators of renal I/R injury, such as IL-18 production and caspase activation (30), is unknown.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

252

231

View full text Add to dashboard Cite

Ischemia/reperfusion (I/R) injury of the kidney is a common cause of acute renal failure (ARF) and is associated with high morbidity and mortality in the intensive care unit. The mechanisms underlying I/R injury are complex. Studies have shown that complement activation contributes to the pathogenesis of I/R injury in the kidney, but the exact mechanisms of complement activation have not been defined. We hypothesized that complement activation in this setting occurs via the alternative pathway and that mice deficient in complement factor B, an essential component of the alternative pathway, would be protected from ischemic ARF. Wild-type mice suffered from a decline in renal function and had significant tubular injury, particularly in the outer medulla, after I/R. We found that factor B-deficient mice (fB−/−) developed substantially less functional and morphologic renal injury after I/R. Furthermore, control wild-type mice had an increase in tubulointerstitial complement C3 deposition and neutrophil infiltration in the outer medulla after I/R, whereas fB−/− mice demonstrated virtually no C3 deposition or neutrophil infiltration. Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

252

231

View full text Add to dashboard Cite

show abstract

“…Products generated upon the cleavage of C3 and C5 (C3a, C3b, C5a, and C5b) have important biological activities (20). C3b, the larger cleavage product of C3, opsonizes bacteria, whereas C3a, the smaller product, is an anaphylatoxin with important functions such as chemotaxis of mast cells and contraction of smooth muscle cells (21)(22)(23)(24). C5b, the larger cleavage product of C5, initiates formation of the cytolytic complex (C5b-9) that causes lysis of bacteria and pathogens, whereas C5a, the smaller product, is a strong chemotactic and spasmogenic anaphylatoxin that mediates inflammatory responses by stimulating neutrophils and phagocytes to the site of injury or infection (21,25).…”

mentioning

confidence: 99%

“…C3b, the larger cleavage product of C3, opsonizes bacteria, whereas C3a, the smaller product, is an anaphylatoxin with important functions such as chemotaxis of mast cells and contraction of smooth muscle cells (21)(22)(23)(24). C5b, the larger cleavage product of C5, initiates formation of the cytolytic complex (C5b-9) that causes lysis of bacteria and pathogens, whereas C5a, the smaller product, is a strong chemotactic and spasmogenic anaphylatoxin that mediates inflammatory responses by stimulating neutrophils and phagocytes to the site of injury or infection (21,25). These products help fight infections, but they also contribute to the pathology of several diseases and conditions such as inflammatory diseases, reperfusion injury, and xenotransplantation rejection (26).…”

mentioning

confidence: 99%

Activation of Complement Component C5

Rawal

Rajagopalan

Salvi

2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Although the initiating complex of lectin pathway (called M1 in this study) generates C3/C5 convertases similar to those assembled by the initiating complex (C1) of the classical pathway, activation of complement component C5 via the lectin pathway has not been examined. In the present study kinetic analysis of lectin pathway C3/C5 convertases assembled on two surfaces (zymosan and sheep erythrocytes coated with mannan (E Man )) revealed that the convertases (ZymM1,C4b,C2a and E Man M1,C4b,C2a) exhibited a similar but weak affinity for the substrate, C5 indicated by a high K m (2.73-6.88 M). Very high affinity C5 convertases were generated when the low affinity C3/C5 convertases were allowed to deposit C3b by cleaving native C3. These C3b-containing convertases exhibited K m (0.0086 -0.0075 M) well below the normal concentration of C5 in blood (0.37 M). Although kinetic parameters, K m and k cat , of the lectin pathway C3/C5 convertases were similar to those reported for classical pathway C3/C5 convertases, studies on the ability of C4b to bind C2 indicated that every C4b deposited on zymosan or E Man was capable of forming a convertase. These findings differ from those reported for the classical pathway C3/C5 convertase, where only one of four C4b molecules deposited formed a convertase. The potential for four times more amplification via the lectin pathway than the classical pathway in the generation of C3/C5 convertases and production of pro-inflammatory products, such as C3a, C4a, and C5a, implies that activation of complement via the lectin pathway might be a more prominent contributor to the pathology of inflammatory reactions.The lectin pathway (1), a more recent discovery of complement, is activated when mannan-binding lectin (MBL), 2 a pattern-recognition molecule, binds to sugars present on the cell surface of microorganisms (2-8). In plasma, MBL circulates in complex with serine proteases called MBL-associated serine proteases (MASPs) (9 -11). We will refer to this complex as M1 in keeping with the complement nomenclature. Three types of MASPs are associated in the proenzyme form with MBL: MASP-1, MASP-2, and MASP-3. The exact function of MASP-1 and MASP-3 has yet to be determined, although MASP-1 has been shown to cleave C3 weakly (12, 13). MASP-2 has been shown to cleave C2 and C4 (12-14). Binding of MBL⅐MASP complexes to sugar residues present on the cell surfaces of microorganisms results in a conformational change of MBL (15, 16), which activates MASP-2. Activated MASP-2 cleaves C4 and C2 resulting in the formation of C3/C5 convertases (C4b,C2a) (17-19).C3/C5 convertases are enzymes that cleave C3 and C5. Products generated upon the cleavage of C3 and C5 (C3a, C3b, C5a, and C5b) have important biological activities (20). C3b, the larger cleavage product of C3, opsonizes bacteria, whereas C3a, the smaller product, is an anaphylatoxin with important functions such as chemotaxis of mast cells and contraction of smooth muscle cells (21-24). C5b, the larger cleavage product of C5, initiates formation ...

show abstract

“…C5a and its degradation product, C5adesArg 74 , exert their various biological activities through interaction with all classes of leukocytes (1), parenchymal cells of the brain (2), kidney (3,4), liver (5), and lung (5), as well as with endothelial cells (6) and smooth muscle cells (7). C5adesArg 74 has a different spectrum of bioactivity than C5a; for example, stimulation of human basophils by C5a mediates secretion of leukotriene C4, interleukin-4, and interleukin-13, whereas C5adesArg 74 only stimulates the production of interleukin-4 and interleukin-13.…”

mentioning

confidence: 99%

C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2

Otto

Hawlisch

Monk

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The anaphylatoxin C5a exerts a plethora of biologic activities critical in the pathogenesis of systemic inflammatory diseases. Recently, we reported on a C5a mutant, jun/fos-A8, as a potent antagonist for the human and mouse C5a receptor (CD88). Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial. Replacements by either hydrophobic or negatively charged amino acids switched the CD88 antagonist jun/fos-A8 to a CD88 agonist. In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg 74 . A jun/fos-A8 mutant in which the jun/ fos moieties and amino acids at positions 71-73 were deleted, A8 ⌬71-73 , blocked C5a and C5adesArg 74 binding to CD88 and C5L2. In contrast, the cyclic C5a C-terminal analog peptide AcF-[OP-D-ChaWR] inhibited binding of the two anaphylatoxins to CD88 but not to C5L2, suggesting that the C5a core segment is important for high affinity binding to C5L2. Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable. In contrast, no C5L2 expression was found on human neutrophils. A8 ⌬71-73 is the first antagonist that blocks C5a and C5adesArg 74 binding to both C5a receptors, CD88 and C5L2, making it a valuable tool for studying C5L2 functions and for blocking the biological activities of C5a and C5adesArg 74 in mice and humans.

show abstract

Characterization of Complement Anaphylatoxins and Their Biological Responses

Cited by 110 publications

References 150 publications

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Activation of Complement Component C5

C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2

Contact Info

Product

Resources

About