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Biomedical subjects

A D Inglot

Publications and source records attributed to A D Inglot.

At least 19 recordsLinked to original sources
PubMed1992

Seleno-organic compounds induce interferon and tumor necrosis factor in human but not in rat or mouse lymphoid cells.

The seleno-organic compounds are highly active in several anti-inflammatory assays performed in mice and rats. However, they differ from the classical non-steroidal anti-inflammatory drugs including indomethacin despite the fact that both types of drugs are inhibitors of prostaglandins and leukotrienes. Furthermore, ebselen and analogs are potent anti-oxidants in many animal cell cultures. The toxicity of the drugs is low because selenium in their structure is not bioavailable. We have discovered that the seleno-organic compounds induce interferon gamma (IFN-gamma), IFN-alpha, tumor necrosis factor alpha (TNF-alpha) and other cytokines in human peripheral blood leukocytes (PBL). Furthermore, the action of the drugs and PHA or Con A was synergistic. However, ebselen and analogs were found to be inactive as the cytokine inducers in cultured rat or mouse lymphoid cells. In contrast to their effects in human PBL, the drugs even inhibited the production of IFN-gamma after stimulation with PHA or Con A. The inhibition was dose dependent. We suggest that the induction of IFN by ebselen and analogs is species specific and it may depend on interaction of the drugs with a specific receptor and/or signal-transducing system present in human but not in some animal cells.

Animals↗
PubMed1992

Simultaneous induction of interferon gamma and tumor necrosis factor alpha by different seleno-organic compounds in human peripheral blood leukocytes.

Ebselen is known as anti-inflammatory and anti-oxidant selenium containing drug. We have synthetized 13 seleno-organic compounds, analogs of ebselen. Seven of them were found to be inducers of interferon gamma (IFN-gamma) and/or tumor necrosis factor alpha (TNF-alpha) in human peripheral blood leukocytes (PBL) cultures. The most active cytokine inducers were: 2-phenyl-1,2-benzisoselenazol-3(2H)-one (1, ebselen), bis [2-(N-phenylcarbamoyl)]phenyl diselenide (7) and bis (2-[N-(2-pyridyl)carbamoyl])phenyl diselenide (8). The amounts of IFN and TNF produced by PBL cultures in response to the seleno-organic compounds were found to be similar to that induced by phytohemagglutinin (PHA). The activities of the seleno-organic compounds were dose-dependent and related to the chemical structure of the drugs suggesting involvement of the specific cytokine-inducer receptor. The simultaneous inductions of IFN-gamma and TNF-alpha were highly correlated, but independent on each other.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Human lymphoid target cells for the cytokine-inducing seleno-organic compounds.

Several seleno-organic compounds including ebselen are known as antiinflammatory and antioxidant agents. They also have glutathione peroxidase-like activity and are inhibitors of leukotrienes and prostaglandins. We have recently discovered that these drugs are inducers of cytokines, mainly interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) and mitogenic interleukins in human peripheral blood leukocytes (PBL) but not in the mouse or rat lymphoid cells. We described a production of IFN-gamma and TNF-alpha by various subsets of PBL stimulated with 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) or bis [2-(N-phenyl-carbamoyl)]phenyl diselenide. IFN-gamma was produced mainly by E-rosette positive lymphocytes. However, the presence of monocytes was required for the optimal production of IFN-gamma. Also soluble mediators released by monocytes enhanced IFN-gamma synthesis. On the other hand, TNF-alpha was produced mainly by the adherent monocytes. Its synthesis was enhanced by the addition of T or B lymphocytes or conditioned medium from the culture of the stimulated lymphocytes. The relative concentrations of the subsets of lymphocytes or monocytes was important for the maximum production of both IFN-gamma and TNF-alpha. High concentration of lymphocytes inhibited the cytokine production.

Adjuvants, Immunologic↗
PubMed1992

Inhaled natural human interferon alpha induces bronchospastic reactions in asthmatics.

There is a relationship between viral infection and aggravation of bronchial asthma symptoms. Viruses belong to the strongest and fast acting inducers of interferon (IFN), which, in turn, may enhance histamine release from effector cells. We have administered IFN intrabronchially to 49 patients suffering from bronchial asthma. The impairment of lung ventilation with significant decrease of forced expiratory volume in one second (FEV1) have been observed in majority of the patients who inhaled crude or purified IFN preparations.

Administration, Inhalation↗
PubMed1991

Mitogenic activity of selenoorganic compounds in human peripheral blood leukocytes.

A variety of organoselenium compounds were originally described as antiinflammatory, antioxidant or glutathione-peroxidase-like agents, and as inhibitors of prostaglandin and leukotriene synthesis. Recently, the compounds have also been found to be inducers of interferon gamma and tumor necrosis factor in human peripheral blood leukocytes (PBL). We evaluated the effects of bis [2-(N-phenylcarboxamido)phenyl] diselenide and Ebselen; 2-phenyl-1,2-benzisoselenazol-3(2H)one, on the incorporation of tritiated thymidine into the DNA of PBL cultured in vitro. Both compounds were mitogenic and this effect was correlated with the expression of interleukin 2 receptor in T-lymphocytes. Therefore, we suggest that the selenoorganic compounds may induce mitogenic cytokines.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Transforming growth factor-beta inhibits the antiviral action of interferons in human embryonic fibroblasts.

Transforming growth factor-beta (TGF-beta) at concentration of 10 ng/ml inhibited the development of the interferon-alpha- (IFN-alpha) or IFN-gamma-induced antiviral state in quiescent human embryonic fibroblasts. The action of the cytokines was dose-related; TGF-beta had no direct effect on the replication of either vesicular stomatitis virus (VSV) or encephalomyocarditis virus (EMCV) used as the challenge viruses in the IFN assays. We suggest that despite the fact that TGF-beta acts mainly as a "negative" growth factor, its interactions with IFNs in the antiviral assays resemble known effects of the typical "positive" peptide growth factors.

Embryo, Mammalian↗
PubMed1991

Combined action of interferons and transforming growth factor beta on the proliferation of human fibroblasts.

The effects of interferons (IFNs) and transforming growth factor-beta (TGF-beta) used alone and in combination on the multiplication of human embryonic diploid fibroblasts were studied. The experimental conditions were standardized and medium containing 2% of a single batch of fetal calf serum, which was almost minimal dose required for good the cell attachment and growth, was used. The observed effects were dose related. IFNs (types alpha, beta, or gamma) at concentration of 1 to 100 U/ml or TGF-beta at concentration of 0.1 to 1.0 ng/ml stimulated the cell multiplication by 20 to 25% when compared to the control cultures incubated without the factors. At higher doses both IFNs (10(2) to 10(5) U/ml) or TGF-beta (1 to 10 ng/ml) inhibited the proliferation of the cells. The antimitogenic action of IFNs and TGF-beta was synergistic. We suggest that IFNs as well as TGF-beta are bifunctional growth regulators although their antimitotic action dominates over their possible growth stimulatory activity. The latter action may be a secondary phenomenon due to interaction of IFNs or TGF-beta with other factors present in cell culture. We have shown that epidermal growth factor (EGF) may increase the growth stimulatory action of low doses of IFN-gamma or TGF-beta.

Cell Division↗
PubMed1991

[The interferon system in chronic brucellosis].

The purpose of the paper was to evaluate activity of interferon system in a group of patients with chronic brucellosis. Trial was performed in 21 persons: 10-with active and 11-with non active disease. "Whole blood test" was used to induce interferon by peripheral blood leucocytes after stimulation with antigens: non specific (NDV, LPS, PHA + PMA) and specific (Brucella). There was no difference between examined and control groups in interferon induction by non specific factors. This indicates correct functions by interferon system in chronic brucellosis. Relatively, after stimulation by specific antigens 4-fold increase of endogenic interferon (alfa and gamma) was observed. These results suggest that chronic brucellosis (active and non active) in still immunologically active and pathological changes depend on delayed hypersensitivity. We conclude, that this method seems to be deciding diagnostic test in latent brucellosis.

Adult↗
PubMed1990

Organoselenides as potential immunostimulants and inducers of interferon gamma and other cytokines in human peripheral blood leukocytes.

A number of organoselenium compounds have been described as anti-inflammatory, antioxidant, glutathione peroxidase-like agents and inhibitors of prostaglandin synthesis. Here we report that bis [2-(N-phenyl-carboxamido)]phenyl diselenide, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (Ebselen) and related compounds are inducers of interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) in human peripheral blood leukocytes. The IFN and TNF response was rapid, occurring within 20 h, and high--up to 1000 and 2000 units ml-1--and was clearly related to the dosage and the structure of the compounds. The action of the compounds and phytohemagglutinin was synergistic. The IFN gamma and TNF production was reduced after removing adherent cells. Although the mode of action of the compounds is not known, they appear to interact directly or indirectly with both adherent and non-adherent leukocytes, and stimulate the synthesis of a set of different cytokines including factors controlling the cell proliferation. Therefore, organoselenides may be regarded as the biological response modifiers.

Adjuvants, Immunologic↗
PubMed1990

Hyporesponsiveness of human alveolar leukocytes to interferon-alpha and interferon-gamma inducers.

Leukocytes were obtained from bronchoalveolar lavages (BAL) of 36 patients including 10 with lung cancer, 15 with inflammatory lung diseases and 11 healthy control patients undergoing diagnostic investigation. The entire alveolar cell population responded weakly to the classic interferon (IFN) inducers: Newcastle disease virus (NDV), phytohemagglutinin (PHA) and lipopolysaccharide (LPS). This refers mainly to normal healthy volunteers. Alveolar leukocytes from patients with inflammatory lung diseases and nonsteroid treated lung cancer responded better to the interferon inducers than did cells from other patients. The IFN-alpha or IFN-gamma response of whole blood leukocytes to the same inducers was 10 to 100-fold higher than that of the alveolar cells. Alveolar macrophages from 6 healthy individuals and 3 patients with inflammatory lung disease were cultured in vitro for 6 days. The IFN response to inducers appears to depend on the origin of the cultured cells. It increased in the initially hyporeactive macrophages from healthy subjects and decreased in the relatively reactive cells from the patients with inflammatory lung diseases. We suggest that the hyporeactivity to IFN induction is a physiological state of the alveolar leukocytes which are a specialized cell population having constant exposure to inhaled agents such as dust, smoke, microorganisms and their by-products. The hyporesponsiveness to IFN induction of the alveolar cells may have an important physiological role in protecting lungs against hyperproduction of cytokines involved in the inflammatory and allergic reactions.

Adult↗
PubMed1990

Antigen-specific and nonspecific interferon response of peripheral blood leukocytes from patients with chronic brucellosis.

Thirty seven blood samples from 21 patients with chronic brucellosis were studied for interferon response to Brucella specific antigens and to the classical IFN inducers. Whole blood technique for IFN induction and bioassay with A549 cells challenged with EMC virus for IFN detection were used. Two different antigen preparations (BRU-1 and BRU-2) used for the serologic diagnosis of brucellosis, stimulated significantly (P less than 0.001) the synthesis of IFN-alpha and IFN-gamma in the whole blood cultures from the patients with chronic brucellosis but not from the control subjects. The detoxified antigen (brucellin) was inactive as the IFN inducer. BRU-1 and BRU-2 antigens induced also low levels of IFN-alpha + IFN-gamma in the short term cultures of the separated peripheral blood leukocytes (5-10 X 10(6) cells/ml) from healthy blood donors. This resembled stimulation of the leukocytes with LPS. Brucellin was inactive in the leukocyte culture. Despite the chronic infection lasting many years the brucellosis patients had apparently intact IFN system because the response of their leukocytes to NDV, PHA + PMA or LPS was not significantly different from that of the healthy blood donors. The importance of the relative balance of the IFN system for the pathogenesis of brucellosis is suggested and contrasted with IFN disfunction in the acquired immune deficiency syndrome.

Adult↗
PubMed1988

Lack of interferon production by dipyridamole.

Dipyridamole, previously reported to be an interferon (IFN) inducer in mice, was evaluated in 43 normal volunteers or cancer patients. At doses ranging from 150 mg orally to 887 mg intravenously, no serum antiviral activity suggesting IFN induction was observed.

Dipyridamole↗
PubMed1988

1,4-naphthoquinone-2-sulfonic acid derivatives coupled to dextran as carriers for interferon.

Three derivatives of 1,4-naphthoquinone-2-sulfonic acid possessing the fragments of Cibacron Blue (CB) were synthesized and bound to Dextran T 2000 by ether binding. Polymers IVD, VD and VID were incubated with interferon (IFN) to obtain complexes: carrier-IFN. It was found that polymer VID has weaker affinity to mouse IFN-beta/alpha and to human IFN-beta than Blue Dextran. The polymers IVD and VD had no affinity to the interferon.

Affinity Labels↗
PubMed1988

Assessment of interferon production in patients with chronic nonviral diseases by whole blood or whole bone marrow techniques.

Hundred and fifty-four samples of heparinized blood from patients with chronic toxoplasmosis, chronic brucellosis, lung diseases, psychiatric affective disorders, healthy individuals and neonates, were obtained. The experimental material included also 14 bone marrow samples from patients with hematological diseases or lung cancer. The whole cell populations were treated with several classical IFN inducers and supernatants were assayed for IFN activity in human lung adenocarcinoma cell line A 549 using VSV or EMC viruses as challenge. The response of WBC to NDV or PHA + PMA was high and remarkably stable in majority of cases except listed below. The levels of IFN induced by LPS were low. The response of WBMC to IFN inducers closely resembled the response of WBC. Low IFN levels in samples of stimulated WBMC from some hematological patients were connected with low cellularity. WBC from psychiatric patients with affective disorders weakly responded to stimulation with NDV. This suggested an existence of deficiency of IFN alpha production connected with affective disorders. Also WBC from cord blood failed to react to PHA + PMA and were poorly responsive to NDV.

Adolescent↗
PubMed1988

Participation of polypeptide proteinase inhibitors in proliferation of fibroblasts.

The polypeptide proteinase inhibitors (PI) isolated from Cucurbitaceae plants, bovine pancreas, lima bean kale seeds and some other sources were assayed in mouse, rat and human cell cultures for possible mitogenic effects. PI stimulated the proliferation of the spare cultures of Balb/c 3T3 and NRK-49F fibroblasts pretreated with trypsin. PI had no effect on [3H]thymidine incorporation by the monolayer cultures of the mouse or rat cells. Also certain human cell lines were unresponsive to PI. The results suggest that PI have growth factor-like activities which are cell and/or species specific.

Animals↗
PubMed1987

Interactions of interferons and transforming growth factors during clonal growth of mouse or human cells in soft agar and in mice.

The mouse fibroblast-like transformed cell line C-243 adapted to growth in suspension was used as a source of virus-induced interferons (MulFN-alpha, beta), and spontaneously produced active growth factors. These factors were purified from C-243 cells grown as tumors in BALB/c mice, and had properties identical to those of TGF-alpha or TGF-beta isolated by others from different tissues. Exogenous TGF-alpha, beta stimulated colony formation by C-243 cells in soft agar, whereas MulFN-alpha, beta inhibited it. Clonal growth of human lung adenocarcinoma A549 cells in soft agar was inhibited as well by human interferons (types alpha, beta, or gamma) as by TGF-beta. Inhibition was dose-related. Pure EGF, which is an analogue of TGF-alpha, diminished the antiproliferative activity of interferons alpha, beta, and gamma in A549 cells. On the other hand, the anti-mitogenic action of IFN-beta and TGF-beta was clearly synergistic. In mice bearing C-243 cell tumors, TGF-alpha, beta stimulated growth, whereas MulFN-alpha, beta inhibited it. Stimulation of tumor growth was also observed after administration of anti-IFN serum that could neutralize endogenous IFN-alpha, beta. The simultaneous administration of MulFN-alpha, beta and TGF-alpha, beta diminished anti-tumor effects of IFN in mice. Our results suggest that both TGFs and IFNs are autocrine, positive or negative growth factors modulating the rate of proliferation and the neoplastic behavior of the cells. The final effects depend on the target-cell sensitivity and on the relative concentration of the various hormone-like factors. Cancer cells overstimulated by TGF-alpha, beta or by EGF may not respond to IFNs.

Adenocarcinoma↗