Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock.
The complement anaphylatoxin C3a, on binding the C3aR, mediates numerous proinflammatory activities. In addition, recent in vitro studies with C3a have implicated C3aR as a possible anti-inflammatory receptor. Because of its possible dual role in modulating the inflammatory response, it is uncertain whether C3aR contributes to the pathogenesis of endotoxin shock. Here, the targeted-disruption of the C3aR in mice is reported. These mice exhibit an enhanced lethality to endotoxin shock with a pronounced gene dosage effect. In addition, the plasma concentration of IL-1beta was significantly elevated in the C3aR(-/-) mice compared with their littermates following LPS challenge. These findings demonstrate an important protective role for the C3aR in endotoxin shock and indicate that, in addition to its traditionally accepted functions in mediating inflammation, the C3aR also acts in vivo as an anti-inflammatory receptor by attenuating LPS-induced proinflammatory cytokine production.
Kildsgaard
J
J
Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston, Houston, TX 77030, USA.
Hollmann
T J
TJ
Matthews
K W
KW
Bian
K
K
Murad
F
F
Wetsel
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology*; D015926:Complement C3a / Q000378:metabolism / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D018390:Gene Targeting / Q000379:methods; D020022:Genetic Predisposition to Disease; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics*; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology* / Q000401:mortality
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a