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Interferon gamma increases in vitro and in vivo expression of C1 inhibitor
GD Heda, S Mardente, L Weiner and AH Schmaier
Thrombosis Research Center, Temple University School of Medicine,
Philadelphia, PA 19140.
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.
Volume 75,
Issue 12,
pp. 2401-2407,
06/15/1990
Copyright © 1990 by The American Society of Hematology
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