Anaphylatoxins: Possible Roles in Disease

Vogt, W.

doi:10.1159/000467894

Cited by 116 publications

(50 citation statements)

References 38 publications

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“…The complement anaphylatoxins C3a and C5a are potent chemotactic agents that help to recruit and activate immune and inflammatory cells (49). In diseases where complement is abnormally activated, C3a and C5a induce the release of various immunoinflammatory mediators and cytokines that contribute to the disease process (11)(12)(13), and inhibitors of complement have significant protective effects on models of these diseases (50,51). This indicates the central role played by these anaphylatoxins in inflammatory and immune pathways.…”

Section: Discussionmentioning

confidence: 99%

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A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff¹,

Arumugam²,

Shiels³

et al. 2003

The Journal of Immunology

109

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The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-d-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-α levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-α inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 99%

“…These components, particularly the anaphylatoxins, are potent inflammatory mediators that are associated with pathology in various disease states (11)(12)(13). The complement system is believed to be activated in patients with IBD and is thought to play a role in disease pathogenesis (3,14).…”

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confidence: 99%

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff¹,

Arumugam²,

Shiels³

et al. 2003

The Journal of Immunology

109

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“…Skp is the third ligand of C5a receptor discovered so far. It surprises us, because the other two ligands are intrinsic chemical mediators; C5a is a well-known chemical mediator of acute inflammation, 1 and the RP S19 dimer has been demonstrated to be a chemical mediator involved in the phagocytic clearance of apoptotic cells. 6,7 Because Skp is widely distributed in gram-negative bacterial species, the recognition of Skp by leukocytes would be of benefit to the innate immunity against gram-negative bacterial pathogens.…”

Section: Discussionmentioning

confidence: 99%

Bacterial Chaperone Protein, Skp, Induces Leukocyte Chemotaxis via C5a Receptor

Shrestha¹,

Shi²,

Tanase³

et al. 2004

The American Journal of Pathology

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C5a receptor has been identified as a leukocyte chemotactic receptor to two intrinsic chemical mediators, C5a and the S19 ribosomal protein dimer, so far. We found an Escherichia coli protein that also induced the chemotactic responses of monocytes and polymorphonuclear leukocytes via the C5a receptor. We identified the E. coli-derived chemoattractant to be Skp by the molecular size and the N-terminal amino acid sequence. Skp is a periplasmic chaperone protein widely present in gram-negative bacterial species. Immunoabsorption experiments indicated that Skp was the major leukocyte chemotactic factor in the E. coli extract. Receptor-antagonizing experiments with analogue peptides of S19 ribosomal protein and C5a receptor is one of the most important leukocyte receptors involving in the inflammatory reaction. C5a receptor was initially identified as the receptor of C5a, which is a 74 amino acid peptide liberated from the ␣-chain of complement C5 by C5 convertases during the complement activation. C5a attracts polymorphonuclear leukocytes (PMNs), monocytes, and many other leukocytes via the C5a receptor. In addition to this, C5a stimulates PMNs via the C5a receptor to release granule contents and to produce radical oxygen species.1 C5a also promotes monocytes/macrophages via the C5a receptor to synthesize interleukin (IL)-1, IL-6, and several other cytokines.2 The C5a receptor gene, which is located on chromosome 19 q13.3-13.4 (from the Genome Database), is also expressed in nonmyeloid cells such as astrocytes and hepatocytes at least under inflamed conditions. Hepatocyte C5a receptor would participate in the acute phase protein synthesis. Besides, we have realized that the S19 ribosomal protein (RP S19) dimer attracts monocytes via the C5a receptor as in the case of C5a.3 RP S19 is a component of the small subunit of ribosome, being composed of 145 amino acid residues. RP S19 is intermolecularly crosslinked by a transglutaminase-catalyzed reaction 4,5 during apoptotic process and the dimer is liberated from the apoptotic cells. 6,7 The RP S19 dimer attracts monocytes/ macrophages and promotes them to phagocytically clear the apoptotic cells from which the chemoattractant molecule has been originated. In contrast to this, the RP S19 dimer antagonizes the C5a receptor-mediated chemotaxis of PMNs. 3Whereas a calculated homology in the amino acid sequence between C5a and RP S19 is only 4%, C5a and the RP S19 dimer activate monocyte C5a receptor by the same interaction mechanism. The C5a receptor, composed of 350 amino acid residues, is a member of the G-protein-coupled 7 transmembrane protein receptor family. The ligand-receptor interaction between C5a or the RP S19 dimer and C5a receptor is a two-step binding process. 8 In the first binding, a basic cluster of the ligand molecules; a cluster three-dimensionally formed by His15, Arg46, and Lys49 of C5a, or a cluster with the Lys41-His42-Lys43 tandem of RP S19, seems to bind to the amino-terminal acidic moiety of C5a receptor, which is composed of several Asp residues ...

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“…peptidoglycan) can activate both the complement system and the contact system of intrinsic coagulation (2,3). Considerable evidence has accumulated that excessive activation of these cascade systems, with release of biologically active peptides (anaphylatoxines and bradykinin), plays a role in the pathophysiology of sepsis, notably Receivedfor publication 7 July 1988 and in revisedform 24 February 1989. when complicated by shock and/or adult respiratory distress syndrome (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

138

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Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (Cl-Inh) (M, 110,000). Elevated iCl-Inh levels (_ 0.13 ,uM) were found in 81% of all patients, sometimes up to 1.6 MM. Levels of iCl-Inh on admission appeared to be of prognostic value: iCl-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iCl-Inh levels up to 0.2,uM was 27%, but in 12 patients with plasma iCl-Inh exceeding 0.44 gM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of Ci-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.

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Anaphylatoxins: Possible Roles in Disease

Cited by 116 publications

References 38 publications

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Bacterial Chaperone Protein, Skp, Induces Leukocyte Chemotaxis via C5a Receptor

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

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