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Regulation of complement factor H in a human liver cell line by interferon-gamma
1Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, USA.
Abstract:
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.
Insights
Interferon-gamma (IFN-gamma) upregulates Factor H mRNA in liver cells. This induction involves both protein synthesis and phosphorylation, suggesting a complex regulatory mechanism.
Area of Science:
- Immunology
- Molecular Biology
- Hepatology
Background:
- Factor H is a key regulator of the alternative complement pathway.
- The liver is the primary site for Factor H synthesis.
- Understanding Factor H regulation is crucial for immune system control.
Purpose of the Study:
- To investigate the regulation of Factor H by interferon-gamma (IFN-gamma) in a human liver cell line.
- To elucidate the molecular mechanisms underlying IFN-gamma-induced Factor H expression.
Main Methods:
- Utilized Hep3b human liver cells as a model system.
- Administered varying concentrations of IFN-gamma and measured Factor H mRNA levels.
- Assessed the role of protein synthesis using cycloheximide (CHX).
- Investigated the involvement of phosphorylation using kinase inhibitors (staurosporine, genistein).
Main Results:
- IFN-gamma significantly increased Factor H mRNA levels, with optimal induction at 50 U/ml.
- Factor H mRNA levels rose within 2 hours, peaking at 24 hours, with a half-life of 3.8 hours.
- Protein synthesis inhibition (CHX) reduced induction by 40%.
- Kinase inhibitors (staurosporine, genistein) markedly inhibited induction (88% and 68%, respectively).
- Complete inhibition was observed with combined CHX and staurosporine treatment.
Conclusions:
- IFN-gamma induces Factor H expression in liver cells through a mechanism dependent on both protein synthesis and phosphorylation.
- The induction likely involves Stat1alpha and a cycloheximide-sensitive protein.
- These findings provide insights into the intricate regulation of complement factor H.
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