[Antiviral and immunomodulating activity of polyprenyl phosphates in viral infections].

Expressed antiviral activity of Fortepren (FP) and Gamapren (GP), polyprenyl phosphate (PPP)-contaning agents, was demonstrated in experiments on mice infected with the human herpes simplex virus, type 1 (HSV1) or the vernal encephalitis virus (VEV). Since both the viral infections are of great social significance, the PPP-containing agents should be considered prospective for the medical practice. The experimental data suggested that both the drugs considerably inhibited the VEV infectiousness in the susceptible cell culture. The quantity of protein E, the main immunogen of VEV, in the culture fluid of the VEV infected cells was shown to be markedly lowered under the effect of FP and GP. It was demonstrated for the first time that FP and GP significantly inhibited evolution of the VEV protein E in the cell culture J-96. The experiments with the infectious rhinotracheitis virus (IRTV) of the corned cattle revealed that FP and GP greatly retarded the HSV1 development in the susceptible cell culture. One of the mechanisms of the antiviral action of the PPP-containing agents was likely the effect on the evolution of the virus proteins in the cells. The impact of FP on production of some key cytokines (CT) was studied on mice with experimental vernal encephalitis (IFN-gamma, IL-4 and IL-12). The content of the above mentioned CT in blood of the mice was determined by the IFA test. Under the normal conditions and in the mice infected with VEV, production of IL-12 and IFN-gamma was shown to be stimulated during the first 3-5 days after the FP administration, whereas in the animals not exposed to FP there was observed stimulation of the IL-4 production during the first 3 days after the contamination, followed by increased production of IL-12 and IFN-gamma.

[The capacity of fusicoccin for inducing the synthesis of early interferon].

The response of human and animal cells to the action of fusicoccin (FC), a fungal metabolite with phytohormonal properties, was evaluated. The capacity of FC for inducing the synthesis of early interferon (IFN), supplied into the blood serum of common white mice, and for enhancing the natural cytotoxic activity of human lymphocytes in vitro was established. The metabolism of actively proliferating monocytic leukemia cells J-96 and human ovarian carcinoma cells CaOv, as well as mouse fibroblasts L-929, was found to be inhibited under the in vitro action of FC. The common character of the mechanisms of action of FC and IFN having antiproliferative and immunomodulating activity is discussed.

[Capacity of fusicoccin for inducing the production of early interferon].

The response of human and animal cells to the action of fusicoccyne (FC), a fungal metabolite with phytohormonal properties, was evaluated. As shown by in vitro studies, FC had the capacity to induce the production of early interferon (IFN) in the blood serum of non-inbred white mice and to enhance the natural cytotoxic activity of human lymphocytes. In vitro experiments also revealed that the action of FC inhibited the metabolism of actively proliferating monocytic leukemia cells J-96 and human ovarian carcinoma cells CaOv, as well as mouse fibroblasts L-929. The common character of the mechanism of action of FC and IFN, having well-known antiproliferative and immunomodulating activity, is discussed.

[Identification of genes induced to chondrocytes by nitric oxide]. / Poisk i identifikatsiia genov, indutsiruemykh v khondrotsitakh pod deistviem okisi azota.

Nitric oxide (NO) acts as a short-lived paracrine factor and selectively activates transcription of certain genes. The spectrum of inducible genes was studied in primary chondrocytes. A cDNA library was obtained by subtraction hybridization with RNAs isolated from rabbit chondrocytes before and after treatment with nitrosoglutathione, an NO-generating agent. Some of the cloned cDNAs were homologous to known mammalian genes and human EST. NO-dependent transcriptional activation was demonstrated for the stromelysin 1 and cyclooxygenase 2 genes and, for the first time, for mcl1 coding for an apoptosis suppressor.

[Relationship between interferon priming effect and functional activity of human blood cells]. / Zavisimost' praimiruiushchego éffekta interferona ot funktsional'noi aktivnosti kletok krovi cheloveka.

Relationship between the priming effects of interferon (IFN)-alpha and -gamma and the standard IFN production by peripheral blood leukocytes was evaluated in 25 volunteers (13 men and 12 women, mean age 35.3 years). Priming of IFN-alpha and IFN-gamma production positively correlated with the standard IFN-alpha and IFN-gamma synthesis, respectively. On the other hand, primed production of IFN-alpha negatively correlated with that of IFN-gamma. Possible role of types I and II IFN interactions in the maintenance of physiological regulatory balance is discussed.

[Cellular sensitivity to the effect of interferon during different forms of viral pathology]. / Kletochnaia chuvstvitel'nost' k deistviiu interferona pri razlichnykh formakh virusnoi patologii.

A new approach to evaluation of interferon (IFN) status of patients with acute respiratory viral infections, herpes, and urogenital infections has been developed. It consists in measurement of IFN-alpha and IFN-gamma production by leukocytes primed with IFN-alpha and IFN-gamma, respectively, and subsequent identification of groups of patients whose lymphocytes differ by their in vitro response to IFN priming: sensitive to IFN-alpha and IFN-gamma; sensitive to IFN-alpha but not to IFN-gamma; sensitive to IFN-gamma but not to IFN-alpha; not sensitive to IFN-alpha and IFN-gamma. Such analysis helps understand the mechanisms of IFN system deficiency in infectious diseases and promotes more effective IFN therapy due to selection of patients whose cells retain in vitro sensitivity to a certain IFN type.

Two pathways of the nitric oxide-induced cytotoxycal action.

Nitric oxide is a diffusible messenger with multiple biological functions. We show here that NO-generating compound, S-nitrosoglutathione (GSNO) induces apoptosis in human chondrocytes and causes necrosis-like cell death in human epithelial CaOv cell line. Pretreatment of chondrocytes with low-dose GSNO or with gamma-interferon enhances their tolerance to the second high-concentration GSNO exposure. On the contrary, in CaOv cells low-dose GSNO pretreatment diminishes the resistance and increases cytolysis at the second GSNO exposure. We conclude that human chondrocytes possess specific and inducible mechanism preventing cell killing by nitric oxide.

Alternative processing of the tryptophanyl-tRNA synthetase mRNA from interferon-treated human cells.

We have analysed the structure of mRNA isoforms of the human gene encoding tryptophanyl-tRNA synthetase (Trp-tRNA synthetase) expressed in the epithelial CaOv cells and MT-4 lymphocytes. The Trp-tRNA synthetase gene is induced by interferon-gamma in both lines and, in MT-4 lymphocytes, also by interferon-alpha. Four Trp-tRNA synthetase mRNA isoforms have different combinations of the first exons IA, IB and II. Two transcription initiation sites (P1 and P2) were detected 90 bp from each other. Processing of the primary transcript initiated from the P1 start site generates the mRNA isoform where exon IA joins to exon II. The other three isoforms are produced by alternative splicing of the primary transcript produced from the P2 start site. Isoform 2 has a 3'-end fragment of exon IA joined to exon II. Isoform 3 contains exons IA and IB. Isoform 4 contains exon IA and exon III and lacks exon II encoding the N-terminus of the Trp-tRNA synthetase. Therefore, the two primary transcripts of the Trp-tRNA synthetase gene differ only in the 5' flank sequence between P1 and P2, and this fragment regulates their processing. Both interferon-alpha and interferon-gamma induce exon IA-containing and exon IB-containing isoforms of the Trp-tRNA synthetase mRNA.

[An interferon inhibitor in regulating the activity of human natural killer cells]. / Ingibitor deistviia interferona v reguliatsii aktivnosti estestvennykh killerov cheloveka.

The action of mouse serum interferon--alpha/beta (IFN) at the dose of 100 U/ml, of its inhibitor (I) at the dose of 8 U/ml as well as of their combination with the above doses on sensitivities of mouse target cells (TC) of sensitive to IFN line L 929 and resistant to the one line MCB in natural cytotoxic reaction was studied. Cytotoxic activity of human natural killer cells was detected in 14 hrs cytotoxic test using 3H-uridine for labelling of TC. IFN, I, and IFN+I were added to cell cultures for 24 hrs at 37 degrees C with following removing of preparations. It has been shown that I abolished protective effect of IFN on TC L 929 whereas the one possessed the protective action on TC MCB in natural cytotoxic reaction. These data confirmed a suggestion about immunoregulatory properties of I which displayed in abolition or realization of protective effect on TC in natural cytotoxic reaction in dependence on initial sensitivity of TC to antiviral IFN action.

[A surface membrane study of human cell lines with different interferon sensitivities]. / Issledovanie poverkhnostnykh membran v liniiakh chelovecheskikh kletok s razlichnoi chuvstvitel'nost'iu k interferonu.

A comparative study of surface membranes of human cell J-96 and J-48 cultures with different sensitivity to alpha/beta interferon (IF). Reduced sensitivity of J-41 cells to IF-alpha/beta was found to be accompanied by a loss of highly specific receptors for IF-alpha, the lack of changes in the cell surface structures upon treatment with IF-alpha/beta, reduced intensity of cell fusion upon successive treatment with IF and polyethylene glycol. The results are discussed in connection with the observed changes in the activity of superoxide dismutase in J-96 and J-41 cell lines after treatment with IF.

[Activity of human natural killer cells against target cells possessing different sensitivity to interferon]. / Aktivnost' estestvennykh killerov cheloveka protiv kletok-mishenei, obladaiushchikh razlichnoi chuvstvitel'nost'iu k interferonu.

The cytotoxic activity of peripheral blood natural killers (NK) against target cells (TC) J-96 and L-929 with high sensitivity to interferon (IFN) action, J-41 and MCB resistant to IFN action and line K-562 labelled by H3-uridine was studied in 14 hrs cytotoxic test. It has been shown that human TC J-96 didn't differ from the J-41 in their sensitivity to NK cytotoxicity and they are strongly resistant to NK than TC K-562. The murine TC L-929 as the human TC didn't differ from the MCB in their sensitivity to NK lysis and had also the same sensitivity to NK as the K-562 cells.

[Interferon-specific cellular receptors in cultured human cells, differing in sensitivity to alpha-interferon]. / Interferon-spetsificheskie kletochnye retseptory v kul'turakh chelovecheskikh kletok, razlichaiushchikhsiia po chuvstvitel'nosti k alpha-interferonu.

The interferon-specific cellular receptors in human cells cultures differing in sensitivity to alpha-interferon have been studied. The J-41 cells resistant to alpha-interferon are practically devoid of receptors highly specific to alpha-interferon. The coefficient of equilibrium and the number of receptors analyzed after Scatchard for J-96 culture of cells are 15.6 x 10(11) M-1 and 210 +/- 90, respectively. Evidently, resistance of J-41 cells to alpha-interferon is connected with the absence of interferon receptors and, as a consequence, inability to interferon-receptor interaction.