Expression and regulation of complement factors H and I in rat and human cells: some critical notes

The complement factors I (FI) and H (FH) are complement regulatory proteins . FI, a highly glycosylated serine protease of 88 kDa cleaves the alpha -ch ains of both complement components Cab and Cob, thereby inactivating them. Complement FH, a glycoprotein of 150 kDa which is composed of 20 short cons ensus repeats synergizes with FI by increasing the affinity of FI for Cab i n the C3b/FH complex by about 15-fold as compared to free Cab. Furthermore, FH prevents factor B from binding to Cab and promotes the dissociation of the C3bBb complex. Both, FI and FH are mainly synthesized in the liver. Acc ording to the quantification of specific mRNA of both factors, various amou nts are produced by different liver cell types, i.e. hepatocytes (HC) and K upffer cells (KC). Investigations of cultured primary HC and KC from rat li ver showed that FI is exclusively synthesized and secreted by HC whereas FH is synthesized by both HC and KC. Using quantitative-competitive PCR for t he quantification of FH-specific mRNA, its constitutive rate of synthesis w as found to be nearly ten times higher in KC than in HC. An extrahepatic so urce of both proteins are human umbilical vein endothelial cells (HUVEC) in which the synthesis of FI is upregulated by IL-6 which is in accord with t he upregulation observed in rat HC and two rat hepatoma cell lines (FAO and H4IIE). Three other proinflammatory cytokines, IL-1 beta, IFN-gamma and TN F-alpha, were alone or in combination, without any effect on the regulation of FI. This demonstrates that the regulation of FI is similar in HUVEC and HC. These results are in contrast to a previously described IFN-gamma -med iated upregulation of FI in HUVEC and suggest, in accordance with other inv estigations on extrahepatic sources of FI (e.g. myoblasts), that IFN-gamma has probably no prominent role in the regulation of FI. Instead, IL-6 appea rs to be the main upregulating cytokine of FI mRNA and of FI protein synthe sis in HC as well as in rat and human hepatoma cells and in HUVEC. Of note are experiments by others and us who could not identify FI-specific mRNA in peripheral blood-derived monocytes, granulocytes, or B- and T-cells of man or rat and in rat peritoneal macrophages. FI-specific mRNA could also not be detected in B- or T-cell lymphoma cells, whereas FH-specific mRNA was ea sily detectable in both human and rat monocytes, and in rat peritoneal macr ophages. These data support the notion that FI in contrast to FH is not exp ressed by cells of the. monocyte-macrophage lineage or by other leukocytes of peripheral blood, at least in the absence of additional stimulants. (C) 2001 Elsevier Science Ltd. All rights reserved.