Interferon gamma increases in vitro and in vivo expression of C1 inhibitor

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-γ) could modulate C1 INH production. Initial studies investigated the effect of IFN-γ 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-γ (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 μg C1 INH antigen per 108 cells (mean ± SEM) to 19 ± 8 μg/108 cells in 8 days. C1 INH produced by HEL cells after IFN-γ stimulation had fully intact kallikrein neutralizing activity. Moreover, conditioned media of IFN-γ-treated HEL cells accumulated more secreted C1 INH in 8 days (6.7 μg/mL/108 cells) than untreated cells (0.6 μg/mL/108 cells). Additional studies were done on plasma specimens from 22 patients with metastatic colorectal carcinoma who received IFN-γ daily for 4 days by intravenous infusion. Before treatment, the mean ± SEM C1 INH levels in these patients was 438 ± 16 μg/mL. At day 10 from the start of the infusion, the plasma C1 INH in these patients increased to 586 ± 32 μg/mL (P