Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component.
The acute-phase response (APR) is regulated by TNF-alpha, IL-1beta, and IL-6 acting alone, in combination, or in concert with hormones. The anaphylotoxin C5a, generated during complement activation, induces in vitro the synthesis of these cytokines by leukocytes and of acute-phase proteins by HepG2 cells. However, there is no clear evidence for a role of C5a or any other complement activation product in regulation of the APR in vivo. In this study, using human C-reactive protein (CRP) transgenic mice deficient in C3 or C5, we investigated whether complement activation contributes to induction of the acute-phase proteins CRP and serum amyloid P-component (SAP). Absence of C3 or C5 resulted in decreased LPS-induced up-regulation of the CRP transgene and the mouse SAP gene. Also, LPS induced both the IL-1beta and IL-6 genes in normocomplementemic mice, but in complement-deficient mice it significantly induced only IL-6. Like LPS injection, activation of complement by cobra venom factor led to significant elevation of serum CRP and SAP in normocomplementemic mice but not in complement-deficient mice. Injection of recombinant human C5a into human CRP transgenic mice induced the IL-1beta gene and caused significant elevation of both serum CRP and SAP. However, in human CRP transgenic IL-6-deficient mice, recombinant human C5a did not induce the CRP nor the SAP gene. Based on these data, we conclude that during the APR, C5a generated as a consequence of complement activation acts in concert with IL-6 and/or IL-1beta to promote up-regulation of the CRP and SAP genes.
Szalai
A J
AJ
Division of Clinical Immunology and Rheumatology, Department of Microbiology, University of Alabama, Birmingham, AL 35294, USA. Alex.Szalai@ccc.uab.edu
van Ginkel
F W
FW
Wang
Y
Y
McGhee
J R
JR
Volanakis
J E
JE
D000210:Acute-Phase Reaction / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics; D003167:Complement Activation; D015936:Complement C5a / Q000008:administration & dosage; D003169:Complement Inactivator Proteins / Q000008:administration & dosage; D003165:Complement System Proteins / Q000172:deficiency / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D004546:Elapid Venoms / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000683:Serum Amyloid P-Component / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000683:Serum Amyloid P-Component; C016310:cobra venom factor; D015936:Complement C5a; D003165:Complement System Proteins; D002097:C-Reactive Protein