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-1 beta, and IL -6 acting alone, in combination, or in concert with hormones. The anaphylot oxin C5a, generated during complement activation, induces in vitro the synt hesis 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 stu dy, 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), Absen ce of C3 or C5 resulted in decreased LPS-induced up-regulation of the CRP t ransgene and the mouse SAP gene. Also, LPS induced both the IL-1 beta and I L-6 genes in normocomplementemic mice, but in complement-deficient mice it significantly induced only IL-6, Like LPS injection, activation of compleme nt 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-1 b eta gene and caused significant elevation of both serum CRP and SAP. Howeve r, in human CRP transgenic IL-6-deficient mice, recombinant human C5a did n ot induce the CRP nor the SAP gene. Based on these data, we conclude that d uring the APR, C5a generated as a consequence of complement activation acts in concert with IL-6 and/or IL-1 beta to promote up-regulation of the CRP and SAP genes.