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Published on: March 2, 2014
Interferon gamma increases in vitro and in vivo expression of C1 inhibitor
G D Heda1, S Mardente, L Weiner
1Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140.
Insights
Gamma interferon (IFN-gamma) boosts C1 inhibitor (C1 INH) production in cells and increases its levels in patients. This cytokine enhances C1 INH expression, a key regulator of inflammatory pathways.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- C1 inhibitor (C1 INH) is a crucial protease inhibitor in the complement and contact systems.
- C1 INH modulates inflammatory responses linked to complement and contact system activation.
- The influence of cytokines on C1 INH production requires further investigation.
Purpose of the Study:
- To investigate whether gamma interferon (IFN-gamma) modulates C1 inhibitor (C1 INH) production.
- To examine the effects of IFN-gamma on C1 INH molecular and protein expression in vitro and in vivo.
Main Methods:
- Human erythroleukemia (HEL) cells were treated with IFN-gamma to assess C1 INH mRNA and protein synthesis.
- Kallikrein neutralizing activity of IFN-gamma-induced C1 INH was evaluated.
- Plasma C1 INH levels were measured in patients with metastatic colorectal carcinoma before and after IFN-gamma treatment.
Main Results:
- IFN-gamma significantly increased C1 INH mRNA and protein expression in HEL cells.
- IFN-gamma treatment led to a 10-fold increase in C1 INH synthesis by HEL cells.
- Plasma C1 INH levels rose significantly in patients receiving IFN-gamma, indicating an in vivo effect.
Conclusions:
- IFN-gamma effectively enhances C1 INH production at both molecular and protein levels in vitro.
- IFN-gamma treatment leads to a significant increase in circulating C1 INH levels in patients.
- These findings suggest IFN-gamma is a potent stimulator of C1 INH expression.
Abstract:
C1 inhibitor (C1 INH) is the major protease inhibitor of the first components of the classic complement system and of the proteases of the Hageman factor pathways. Since C1 INH may modulate inflammatory reactions associated with complement and contact system activation, we sought to determine if the cytokine gamma interferon (IFN-gamma) could modulate C1 INH production. Initial studies investigated the effect of IFN-gamma on the molecular and protein expression of C1 INH in human erythroleukemia (HEL) cells. HEL cells constitutively expressed the 2.1 kb mRNA for C1 INH. IFN-gamma (50 to 1,000 U/mL), but not interferon alpha or beta, increased twofold the amount of C1 INH mRNA expressed within HEL cells. Similarly, this cytokine increased HEL cell C1 INH synthesis of a 105 Kd protein 10-fold, from 1.9 +/- 0.5 microgram C1 INH antigen per 10(8) cells (mean +/- SEM) to 19 +/- 8 micrograms/10(8) cells in 8 days. C1 INH produced by HEL cells after IFN-gamma stimulation had fully intact kallikrein neutralizing activity. Moreover, conditioned media of IFN-gamma-treated HEL cells accumulated more secreted C1 INH in 8 days (6.7 micrograms/mL/10(8) cells) than untreated cells (0.6 microgram/mL/10(8) cells). Additional studies were done on plasma specimens from 22 patients with metastatic colorectal carcinoma who received IFN-gamma daily for 4 days by intravenous infusion. Before treatment, the mean +/- SEM C1 INH levels in these patients was 438 +/- 16 micrograms/mL. At day 10 from the start of the infusion, the plasma C1 INH in these patients increased to 586 +/- 32 micrograms/mL (P less than .0001). The extent of rise of plasma C1 INH after IFN-gamma treatment was independent of dose from 0.01 to 40 U/m2. After 30 days, the mean plasma C1 INH levels decreased to 502 +/- 27 micrograms/mL. These combined studies indicate that IFN-gamma can increase C1 INH protein expression in vitro and in vivo.
