PubMed · 9719138
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P Warwicker, J A Goodship, T H Goodship. 1998. Factor H--US?. https://doi.org/10.1093/ndt%2F13.8.1921
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Complement factor H is a potent inhibitor of alternative pathway complement activation. The factor H gene, a member of the regulators of complement activation (RCA) gene cluster, encodes two plasma proteins, one 150 kilodaltons (kDa) and one 43 kDa. Homozygous deficiency of factor H results in low plasma levels of complement factor B and C3 and depletion of the terminal complement proteins C5-C9; heterozygotes may have reduced or normal levels of factor B, C3, and C5-C9. Although factor H deficiency is infrequently reported, it has been associated with a number of types of renal disease, the most common being atypical membranoproliferative glomerulonephritis and idiopathic (non-diarrhea-associated) hemolytic uremic syndrome (HUS). The molecular defects responsible for factor H deficiency have been described in only two cases; clearly more research is needed in this area. The possible role of factor H deficiency or dysfunction in the pathogenesis of HUS is discussed.
The factor H gene family provides a prime example of a multidomain multifunctional protein family whose individual members are defined by conserved common structural elements and display diverse but often overlapping functions. The six identified members of this protein family represent secreted plasma proteins that are primarily synthesized in the liver. Here, we summarize the current understanding of the function of these proteins and suggest a common role in complement control. Factor H is the best characterized member and acts as a complement regulator. The protein displays cofactor activity for factor I in the degradation of the central complement component C3b, acts as a decay accelerating factor for the C3 convertase, C3bBb and is a competitor for factor B binding to C3b. Factor H is a multifunctional protein and displays functions outside the complement system: it binds to the cellular integrin receptor (CD11b/CD18), interacts with cell surface glycosaminoglycans and also binds to the surface of certain pathogenic microorganisms. In addition, factor H has several binding sites for the C3 protein. The factor H-like protein 1 (FHL-1) or reconectin shares the complement regulatory functions with factor H and interacts with heparin. The protein displays cell spreading activity and binds to the N-terminus of the streptococcal M protein. The function of the factor H-related proteins (FHR-1 to FHR-4) is currently under investigation. These proteins are differently distributed. Three proteins (FHR-1, FHR-2 and FHR-4) are constituents of lipoproteins, while FHR-3 interacts with heparin. Binding to C3b and C3d has been demonstrated for FHR-3 and FHR-4 and the two proteins display a cofactor related activity.
Factor H is a regulatory protein of the alternative pathway of complement activation. The liver is the major site of synthesis. We have used the Hep3b human liver cell line as a model for examining its regulation by interferon-gamma (IFN-gamma). The maximal response was achieved at 50 U/ml of IFN-gamma. An increase in H mRNA was observed as early as 2 h after addition of IFN-gamma; the response peaked at 24 h. The half-life of H mRNA in the presence of IFN-gamma was 3.8 +/- 0.8 h. The increase in H mRNA by IFN-gamma was partly dependent on protein synthesis, as cycloheximide (CHX) reduced the response by 40% and the level of H mRNA decreased in a dose-dependent manner with increasing concentrations of CHX. Phosphorylation events were also important in this induction because the kinase inhibitors staurosporine and genistein inhibited the induction of H mRNA by 88% and 68%, respectively. The induction could be inhibited completely when Hep3b cells were treated with CHX and staurosporine. Thus induction of factor H by IFN-gamma apparently involves two factors. One is likely to be Stat1alpha and the other is a CHX-sensitive protein.