Isoforms of human C4b-binding protein. II. Differential modulation of the C4BPA and C4BPB genes by acute phase cytokines

Human C4b-binding protein (C4BP) controls activation of the complement system and inactivates the anticoagulant vitamin K-dependent protein S using two distinct polypeptides known as C4BP alpha and C4BP beta, respectively. C4BP presents three isoforms, alpha 7 beta 1, alpha 7 beta 0, and alpha 6 beta 1, the proportion of which depends on the relative levels of C4BP alpha and C4BP beta. To better understand the regulation of C4BP during the acute phase response we analyzed the C4BP isoforms in 23 serial samples of acute phase patients and characterized the effect of various acute phase cytokines on the expression of the C4BPA and C4BPB genes using Hep3B cells. We show that the elevation of C4BP during acute phase response leads to changes in the proportion of the C4BP isoforms. However, there are striking differences among acute phase individuals. Some of them present a pattern of induction that primarily affects the alpha 7 beta 0 isoform, whereas others present the opposite situation, increasing the C4BP beta-containing isoforms. In vitro studies demonstrate that IL-6, IL-1 beta, and INF-gamma increase the levels of both C4BP alpha- and C4BP beta-mRNAs, whereas TNF-alpha down-regulates these mRNAs. INF-gamma shows, in addition, a differential effect on the C4BP alpha- and C4BP beta-mRNAs. Differential modulation of the C4BPA and C4BPB genes has been postulated as an efficient mechanism to maintain steady concentrations of C4BP beta when C4BP is induced. A synergistic 10-fold induction of C4BP alpha-mRNA, but a marginal increase of C4BP beta-mRNA, was observed when INF-gamma was used together with TNF-alpha, suggesting that association of these cytokines is critical to avoid elevation of C4BP beta during the acute phase induction of C4BP.