Virus-induced Interferon Production Research Articles

37] Induction of interferon by bacterial endotoxin

Publisher Summary Interferon (IF) induced by endotoxin (EII) appears more rapidly in the circulation than virus-induced interferon. EII, however, is not previously stored in the cells, but is synthesized in response to specific stimuli and after synthesis of specific RNA and protein. Continuous cell cultures have not been reported to produce EII. EII is produced by the animal body or by lymphoid cells and macrophages freshly harvested from the animal body. Lower temperatures are appropriate for cells to produce EII in a culture medium than are required for virus-stimulated IF production. The optimum temperature for the stimulation of peritoneal leukocytes with Newcastle disease virus to produce IF in vitro is 40°, but 22-26° is optimal to produce EII. There are various treatments that reduce EII production: injection of corticosteroids, is adrenalectomy, injection of olive oil emulsion, laparotomy, is and infusion of air into the peritoneal cavity. The kinds of treatment will have either no influence or an inhibitory effect on virus-induced IF production.

Virus-Induced Interferon Production by Human Macrophages

Abstract The presence of interferon during viral infection in humans has been associated with the onset of the recovery process. The identity of the cell responsible for production of interferon in response to live virus has not been determined. Human peripheral blood mononuclear leukocytes, highly purified macrophages, and highly purified lymphocytes were exposed in vitro to influenza A virus. Interferon activity was detectable in the supernatant culture fluids of virus-exposed mononuclear leukocytes by 24 hr, was maximum by 72 to 96 hr, and declined thereafter. In each of eight experiments, supernatant fluid of virus-exposed macrophages contained interferon (100 to 800 units/ml, median 200 units/ml), but in none of the experiments was interferon detected in the supernatant fluid of control macrophages or virus-exposed or control lymphocytes. The interferon had characteristics of classical, Type I, interferon, and its activity was neutralized by rabbit antihuman leukocyte interferon globulin. Appearance of interferon activity in the supernatant fluid could not be attributed to cell death with release of preformed material. Adding lymphocytes to macrophages resulted in no increase in interferon activity in supernatant fluids in response to virus exposure, compared to macrophages alone. The results suggest a mechanism by which human macrophages may play an important role in human defense.

Absence of virus-induced lymphocyte suppression and interferon production in multiple sclerosis

Lymphocytes from normal adult donors exposed in vitro to inactivated measles virus were found to exert significant suppression (33.9%) of the concanavalin A responses of cryopreserved, autochthonous responder cells. In marked contrast, lymphocytes from multiple sclerosis patients exhibited significantly reduced suppression (1.5%), and in 80% of cases failed to suppress at all. The degree of suppression increased slightly with age of the patient but did not vary with the clinical stage of disease. There was no apparent genetic restriction of suppressor activity. Although specificity of this phenomenon for measles virus has not been established, no differences in the responses of lymphocytes from normal or multiple sclerosis patient donors were found with subacute sclerosing panencephalitis, Sendai, canine distemper, mumps, or influenza viruses. Supernates of measles-treated lymphocytes from normal donors possessed both suppressive and antiviral activities. Both activities were resistant to pH 2 treatment and were neutralized by an anti-human leukocyte interferon antiserum, strongly suggesting that interferon (probably type I) was the mediator of suppression. Consistent with their inability to suppress concanavalin A responses, lymphocytes from multiple sclerosis patients failed to produce significant amounts of interferon in response to measles challenge in vitro. These results extend previous observations that multiple sclerosis patients are unable to respond appropriately to measles virus antigen in vitro.

Interferon induction in human cell cultures by small molecular inducers (tilorone and acridines).

Attempts were made to stimulate interferon production in human cell cultures by two related acridin drugs, mepacrine and Acranil. Tilorone was included for comparison. In human embryo lung fibroblasts and in normal human leukocytes only tilorone stimulated some interferon production. All three drugs stimulated modest interferon production in two lymphoblastoid cell lines. All three drugs enhanced the Sendai virus-induced interferon production in lymphoblastoid cells.

Influenza virus-induced interferon production in mouse spleen cell culture: T cells as the main producer

Interferon production by spleen cells from unimmunized C3H mice challenged in vitro with influenza virus AO/PR8 was investigated. Glass-nonadherent cells (lymphocytes) produced significant levels of interferon, although cocultivation of glass-adherent macrophages was needed for optimal production. Treatment of the cells with antithymocyte serum and complement markedly reduced the interferon production. When glass-nonadherent cells were fractionated on a nylon wool column, the T-cell-enriched fraction consistently produced more interferon than the B-cell-enriched fraction. It is concluded that T cells are an important producer of interferon in spleen cell cultures from normal mice upon challenge with influenza virus, although non-T cells (macrophages and B cells) also may produce interferon under suitable conditions.

Marked enhancement of interferon production in 5-bromodeoxyuridine treated human lymphoblastoid cells

MANY human lymphoblastoid cells produce low levels of interferon spontaneously1–5 and this has been attributed to the presence of the Epstein—Barr virus (EBV) in such cells6–7. No clear relationship has been established, however, between the presence of EBV and spontaneous interferon production8. Since the latent EBV genome contained in human lymphoblastoid cells can be activated by treatment of these cells with halogenated pyrimidines9,10 or inhibitors of protein synthesis11 we determined the effect of 5-bromodeoxyuridine (BrdU) on interferon production in these cells in relation to the induction of EBV. Previous studies on the effect of halogenated pyrimidines on interferon production have yielded conflicting results ranging from no effect12–14 to inhibition15, or slight stimulation15,16. We report here that BrdU markedly increases both spontaneous and virus-induced interferon production in three human lymphoblastoid cell lines, without any apparent correlation with EBV induction.

Leukocyte Interferon Production, RNA Synthesis, and PHA Response in Patients With Infectious Mononucleosis

Abstract Sequential measurements of in vitro Newcastle disease virus-induced interferon (IF) synthesis, spontaneous RNA synthesis, and PHA-induced blastic transformation were made in leukocytes derived from ten patients with infectious mononucleosis (IM). The median leukocyte IF production on the day of diagnosis was found to be significantly depressed, 35 international units (IU) IF per 2 x 106 leukocytes, in comparison to a median titer of 463 IU after recovery (p < 0.002) or to a median of 406 IU found in 52 cultures from normal healthy individuals. No spontaneous production of leukocyte IF or circulating serum IF was noted. An increased rate of spontaneous leukocyte RNA synthesis during the first 2 hr of culture was noted in nine of the ten subjects (p < 0.001). Four of the ten patients showed a markedly defective response to PHA after 96-144 hr in culture. A suggestive, but not statistically significant, correlation was noted between increased spontaneous RNA synthesis, defective late PHA transformation, and defective virus-induced IF production. All defects persisted during the 1-wk study period and were resolved after recovery. We conclude that major temporary alterations occur in several parameters of leukocyte function in IM.