IFN-γ In Group Research Articles

Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis.

Interferon gamma (IFN-gamma) inhibits in vitro the activation of hepatic stellate cells (HSC), the primary extracellular matrix-producing cells in liver fibrosis. This study was undertaken to determine in vivo the effect of IFN-gamma in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an early response to cell injury. Rats were killed after 1 or 3 weeks of treatment with DMN, IFN-gamma, DMN + IFN-gamma, or saline. Immunohistochemistry was used to identify proliferating (desmin-positive/bromodeoxyuridine (BrdU)-positive cells) and activated (alpha-smooth-muscle actin [alpha-SMA]-positive cells) HSCs. Collagen deposition was determined colorimetrically and by morphometry. The parenchymal extension of desmin- and actin-positive cells and of fibrotic tissue was measured by point-counting technique and expressed as a percentage of area. Western blot was used to determine laminin and fibronectin accumulation. The levels of messenger RNA (mRNA) for procollagen type I, fibronectin, and laminin were evaluated by Northern blot. No differences were observed in rats treated with either saline or IFN-gamma alone. IFN-gamma reduced HSC activation induced by liver injury, as shown by the decreased number of proliferating HSC and the reduction of parenchymal area occupied by alpha-SMA-positive cells observed in DMN + IFN-gamma-treated animals compared with the DMN group. This was associated with reduced collagen, laminin, and fibronectin accumulation and lower levels of mRNA for procollagen type I, fibronectin, and laminin in the DMN + IFN-gamma group. Thus, this study indicates that IFN-gamma reduces extracellular matrix deposition in vivo by inhibition of HSC activation.

放射線およびｉｎｔｅｒｆｅｒｏｎ‐γがマウスへん平上皮癌細胞のＬＡＫおよびＣＴＬ感受性に与える影響に関する研究

The susceptibility of a mouse squamous cell carcinoma cell line to lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL) was examined in terms of major histocompatibility complex (MHC) class I expression after various treatments with γ-rays and interferon-γ(IFN-γ). The original NR-S 1 cells were squamous cell carcinomas of C 3 H/He mice; these were used as target cells. The NR-S 1 cells were previously treated with (1) irradiation with 10 Gys of γ-rays, (2) 100 U/ml of IFN-γ, (3) a combination of γ-rays and IFN-γ, or (4) citric acid at pH 3. The highest expression of MHC class I was obtained in the combination group, followed by the IFN-γ and γ-ray groups. The lowest expression was obtained in the citric acid group. As for evidence of adhesion molecules, ICAM-1 was enhanced slightly in the IFN-γ group, but ICAM-2 was not enhanced in any group.LAK cells were obtained from the splenic lymphocytes of C3H/He, C57BL/6 or BALB/c mice, and incubated with rIL-2 for 3 days. These LAK cells showed 17-27% cytotoxicity against P815 cells, 69-75% against YAC-1 cells, and about 30% against untreated NR-S 1 cells. The target cells in the combination group were the most resistant to LAK cells, and those in the citric acid group were more sensitive than the untreated cells. There was no significant difference in activities among the three strains of mice. Anti-CD 8 antibody or anti-asialo GM 1 antibody was intra-peritoneally administered to these three strains of mice, and the spleen cells were collected. The cytotoxicity of LAK cells from the mice given anti-CD 8 antibody was similar to that of the untreated mice.In contrast, treatment with anti-asialo GM 1 antibody decreased the cytotoxic activities in all groups. These findings suggest a negative correlation between MHC class I expression and the susceptibility of NR-S 1 to LAK cells. The killer activity was predominantly due to asialo-GM1+ cells.CTL were prepared from untreated C3H/He mice spleen cells. They were incubated with inactivated NR-S 1 cells for 7 days and cultured again with rIL-2 (5 JRU/ml) for 7 days. Although the cytotoxicity of CTL was lower than the LAK activity, it increased in direct proportion to the expression of MHC class I. These findings suggest that CTL would be most effective for adoptive immunotherapy when combined with radiotherapy or cytokine therapy.

Double blind controlled phase III multicenter clinical trial with interferon gamma in rheumatoid arthritis

The controlled clinical trial reported here is part of a multicenter clinical and basic research project, sponsored by the German Federal Minister of Science and Technology, directed by a standing commission of the president of the Max-Planck-Gesellschaft, and coordinated by the Max-Planck-Institut fur Biochemie, Munchen. Overall, 249 patients with rheumatoid arthritis (RA) were enrolled by 16 participating hospitals. In addition to NSAID treatment, patients were randomly given either interferon gamma (IFN-γ) or placebo. In the IFN-γ group, 107 patients were evaluated and in the control group, 116 patients were evaluated. The response rate after 3 months of treatment, according to joint pain indexes, was significantly higher in the IFN-γ group with an error probability of 1%. IFN-γ was able to reduce the quantity of corticosteroids administered. Compared with the control group, the IFN-γ group benefited considering all parameters measured. Most important side effects were transient fever and transient influenza-like symptoms; all other adverse events were comparable in both groups.

Effects of IFN-γ on IL-18 Expression in Pregnant Rats and Pregnancy Outcomes.

The present study focused on establishing the effects of interferon-gamma (IFN-γ) on interleukin-18 (IL-18) expression patterns and pregnancy outcomes in pregnant rats. Pregnant rats at the post-implantation stage were randomized into control, low IFN-γ (L-IFN-γ) and high IFN-γ groups (H-IFN-γ) that received normal saline, 100 IU/g of IFN-γ and 500 IU/g of IFN-γ vaginal muscular injection, respectively. The effects of IFN-γ on IL-18 expression and pregnancy outcomes were assessed systematically using several methods, including immunohistochemistry streptavidin-perosidase (SP), image pattern analysis, enzyme-linked immune-sorbent assay (ELISA), whole blood count (WBC) count, microscopy and visual observation. IL-18 was detected in the uteri of all pregnant rats, and mainly distributed in the endometrium, decidual cells, vascular endothelium and myometrium. Immunohistochemistry and image pattern analyses revealed significantly lower IL-18 expression in the H-IFN-γ group compared to the L-IFN-γ and control groups (p<0.01), indicating that high doses of IFN-γ induce downregulation of IL-18 in the uterus of pregnant rats. ELISA results disclosed that IL-18 expression in peripheral blood of the H-IFN-γ group was lower than that of the L-IFN-γ group (p<0.05), and significantly reduced compared to the control group (p<0.01). Moreover, the number of peripheral leukocytes in the H-IFN-γ group was significantly higher than those in the control and L-IFN-γ groups (p<0.01). Morphology analysis showed no evident differences between the L-IFN-γ and control groups. However, for the H-IFN-γ group, uterine mucosa bleeding, necrosis and excoriation were observed using microscopy. Visual observation revealed marroon, swelling, crassitude and no embryo in the uterus, which are obvious indicators of abortion. These results indicate that IFN-γ plays a regulatory role in IL-18 expression in the uterus and peripheral blood of pregnant rats at the post-implantation stage. Moreover, high levels (500 IU/g) of IFN-γ influence normal pregnancy at the early stages in rats by downregulating IL-18 expression in the uterus and peripheral blood and increasing the number of peripheral leukocytes, consequently triggering termination of pregnancy.