C5a-mediated release of interleukin 6 by human monocytes

Scholz, Wolfgang; McClurg, Mike R.; Cardenas, Gustavo J.; Smith, Mark D.; Noonan, Daniel J.; Hugli, Tony E.; Morgan, Eric Lease

doi:10.1016/0090-1229(90)90043-p

Cited by 141 publications

(65 citation statements)

References 34 publications

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“…Recently, several animal studies using C3aR-genetically disrupted mice and naturally defective guinea pigs indicated a role for C3a in airway hyperresponsiveness after Ag exposure without any influence on cellular infiltration (13,14). However, another potent anaphylatoxin, C5a, remains controversial with respect to its role in allergic asthma, although C5a is important in various human diseases through its diverse actions including chemotactic activity directed to neutrophils, monocytesmacrophages, and eosinophils; direct bronchoconstriction through its receptor on airway epithelial cells; and/or indirect action through the synthesis and release of various cytokines and chemical mediators (15,16). It was recently suggested that BALFs obtained from asthmatic patients contain C5a/C5a desArg, one of the most prominent neutrophil chemotactic factors (17).…”

mentioning

confidence: 99%

Contribution of Anaphylatoxin C5a to Late Airway Responses After Repeated Exposure of Antigen to Allergic Rats

Abe¹,

Shibata

Akatsu

et al. 2001

The Journal of Immunology

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We attempted to elucidate the contribution of complement to allergic asthma. Rat sensitized to OVA received repeated intratracheal exposures to OVA for up to 3 consecutive days, and pulmonary resistance was then estimated for up to 6 h after the last exposure. Whereas the immediate airway response (IAR) in terms of RL tended to decrease in proportion to the number of OVA exposures, late airway response (LAR) became prominent only after three. Although premedication with two kinds of complement inhibitors, soluble complement receptor type 1 (sCR1) or nafamostat mesylate, resulted in inhibition of the IAR after either a single or a double exposure, the LAR was inhibited after the triple. Premedication with a C5a receptor antagonist (C5aRA) before every exposure to OVA also inhibited the LAR after three. Repeated OVA exposure resulted in eosinophil and neutrophil infiltration into the bronchial submucosa which was suppressed by premedication with sCR1 or C5aRA. Up-regulation of C5aR mRNA was shown in lungs after triple OVA exposure, but almost no up-regulation of C3aR. Pretreatment with sCR1 or C5aRA suppressed the up-regulation of C5aR expression as well as cytokine messages in the lungs. The suppression of LAR by pretreatment with sCR1 was reversed by intratracheal instillation of rat C5a desArg the action of which was inhibited by C5aRA. In contrast, rat C3a desArg or cytokine-induced neutrophil chemoattractant-1 induced cellular infiltration into the bronchial submucosa by costimulation with OVA, but these had no influence on the LAR. These differences might be explained by the fact that costimulation with OVA and C5a synergistically potentiated IAR, whereas that with OVA and either C3a or cytokine-induced neutrophil chemoattractant-1 did not. C5a generated by Ag-Ab complexes helps in the production of cytokines and contributes to the LAR after repeated exposure to Ag.

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confidence: 99%

Contribution of Anaphylatoxin C5a to Late Airway Responses After Repeated Exposure of Antigen to Allergic Rats

Abe¹,

Shibata

Akatsu

et al. 2001

The Journal of Immunology

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“…Neutrophils [40] and macrophages [41] express IL-6 upon stimulation with C5a, and production of this cytokine was attenuated when C5a was blocked by Whole-paw homogenates were analysed for protein levels of a range of inflammatory markers using multiplex analysis. yAnti-C5aR-treated group compared to IgG2a-treated group 60 h after single-dose treatment, t-test, n ¼ 10.…”

Section: Discussionmentioning

confidence: 99%

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

et al. 2015

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(2015) Treatment with anti-C5aR mAb leads to earlyonset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model, Autoimmunity, 48:7, 460-470, DOI: 10.3109/08916934.2015 Department of Cell Biology, Novo Nordisk A/S, Beijing, China AbstractBlockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-type hypersensitivity arthritis (DTHA) model to study the very early effects of a blocking, non-depleting anti-C5aR mAb on joint inflammation with treatment synchronised with disease onset, an approach not previously described. The DTHA model is a single-paw inflammatory arthritis model characterised by synchronised and rapid disease onset driven by Tcells, immune complexes and neutrophils. We show that a reduction in paw swelling, bone erosion, cartilage destruction, synovitis and new bone formation is apparent as little as 60 h after administration of a single dose of a blocking, non-depleting anti-mouse C5aR mAb. Importantly, infiltration of neutrophils into the joint and synovium is also reduced following a single dose, demonstrating that C5aR signalling during the early stage of arthritis regulates neutrophil infiltration and activation. Furthermore, the number of T-cells in circulation and in the draining popliteal lymph node is also reduced following a single dose of anti-C5aR, suggesting that modulation of the C5a/C5aR axis results in effects on the T cell compartment in inflammatory arthritis. In summary, these data demonstrate that blockade of C5aR leads to rapid and significant effects on arthritic disease development in a DTHA model strengthening the rationale of C5aR-blockade as a treatment strategy for RA, especially during the early stages of arthritis flare.

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“…Further, both proteins are able to prime macrophages and enhance their susceptibility to HIV infection (48). Therefore, C5a desArginduced cell responses are critically dependent on the type of cell and response studied (7)(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these observations over time shaped the concept of C5a desArg being the product of a quick "deactivation" of the potent C5a in circulation. Historically, however, C5a desArg has been found to induce robust cell responses via C5aR signaling both in vivo and in vitro, yet this activity appears to be dependent on the experimental context and readout as well on the cell type (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

C5aR-dependent cell activation by physiological concentrations of C5a-desArg: Insights from a novel label-free cellular assay

et al. 2012

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The complement anaphylatoxins C3a, C5a, and C5a desArg play critical roles in the induction of inflammation and the modulation of innate and acquired immune responses after binding to their G protein-coupled receptors, C3aR and C5aR. The role of C5a desArg in inducing cell activation has been often neglected, since the affinity of C5a desArg for C5aR has been reported to be much lower than that of C5a. We have used a novel label-free cellular assay to reassess the potential of C5a desArg to induce activation of transfected and primary immune cells. Our results indicate that physiological levels of C5a desArg induce significant levels of cell activation that are even higher than that achieved by stimulating cells with analogous concentrations of C5a. Such activation was strictly dependent on C5aR, since it was completely abrogated by PMX-53, a C5aR antagonist. Pharmacological inhibition of specific G proteins located downstream of C5aR indicated differential involvement of G α proteins upon C5aR engagement by C5a or C5a desArg . Further, mass spectrometric characterization of plasma-derived C5a and C5a desArg provided important insight into the post-translational modification pattern of these anaphylatoxins, which includes glycosylation at Asn 64 and partial cysteinylation at Cys 27 . While the context-specific physiological contribution of C5a desArg has to be further explored, our data suggest that C5a desArg acts as a key molecule in the triggering of local inflammation as well as the maintenance of blood surveillance and homeostatic status.

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C5a-mediated release of interleukin 6 by human monocytes

Cited by 141 publications

References 34 publications

Contribution of Anaphylatoxin C5a to Late Airway Responses After Repeated Exposure of Antigen to Allergic Rats

Contribution of Anaphylatoxin C5a to Late Airway Responses After Repeated Exposure of Antigen to Allergic Rats

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

C5aR-dependent cell activation by physiological concentrations of C5a-desArg: Insights from a novel label-free cellular assay

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