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PubMedDate not supplied

Effect of mouse interferon alpha/beta on the expression of H-2 (class I) antigens and on the levels of 2'-5' oligoadenylate synthetase activity in interferon-sensitive and interferon-resistant Friend leukemia cell tumors in mice.

DBA/2 mice were injected intraperitoneally (i.p.) with interferon-sensitive 745 or interferon-resistant 3C1-8 Friend erythroleukemia cells (FLC) and then injected i.p. with mouse interferon alpha/beta. Interferon enhanced the expression of histocompatibility (H-2) antigens on individual 745 FLC within the peritoneum, but did not alter the expression of H-2 antigens on individual 3C1-8 FLC. Likewise, interferon treatment resulted in an increase in the level of 2'-5' oligo-adenylate (2-5A) synthetase activity in 745 FLC, but did not affect the level of activity in 3C1-8 FLC. These results provide evidence that the phenotype of interferon sensitivity or resistance of FLC does not change within the peritoneum. An incidental finding was that the basal level of 2-5A synthetase activity of in vivo passaged 745 cells was greater than that of 3C1-8 FLC. The finding that injection of mice bearing 745 FLC with antibody to mouse interferon alpha/beta reduced the level of 2-5A synthetase activity in these cells, but did not alter the level of 2-5A activity in 3C1-8 FLC, suggests that endogenous interferon in the peritoneum may have been the responsible factor.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Gene induction by interferons: functional complementation between trans-acting factors induced by alpha interferon and gamma interferon.

HeLaM is a variant cell line in which the transcriptional induction of many genes by alpha interferon has special characteristics (Tiwari et al., Mol. Cell. Biol. 8:4289-4294, 1988). The same characteristics were also displayed for induced transcription of a permanently transfected chimeric gene containing the interferon-stimulated response element of gene 561. For understanding the molecular basis of the special requirements of HeLaM cells, an analysis of the interferon-stimulated gene factors (ISGF) was undertaken. By using gel shift assays, it was shown that the activation of ISGF3 by alpha interferon treatment of HeLaM cells had characteristics identical to those of induced transcription: inhibition by 2-aminopurine and the need for ongoing protein synthesis which was obviated by pretreating the cells with gamma interferon. Upon mixing in vitro the cytoplasmic fraction of gamma interferon-treated HeLaM cells with that of cells treated with alpha interferon and cycloheximide, active ISGF3 was reconstituted, presumably through complementation of two components, ISGF3 gamma and ISGF3 alpha, present in the two respective fractions. Because, unlike other cells, untreated HeLaM cells did not contain detectable levels of either component, we could induce them individually and study their independent properties. Induction of ISGF3 gamma but not of ISGF3 alpha needed ongoing protein synthesis and was blocked by 2-aminopurine. Once induced, ISGF3 gamma was active for 24 h and was present in both the nuclear and cytoplasmic fractions. Activated ISGF3 alpha, on the other hand, did not translocate to the nucleus in the absence of ISGF3 gamma, and in the cytoplasm its activity decayed within 2 h of its activation. In reference to our working model, all of the above observations indicate that ISGF3 gamma is the product of signal 1 and ISGF3 alpha is the product of signal 2.

Base Sequence↗
PubMed1990

[The immunomodulating action of interferon. The change in the rosette-forming activity of human blood lymphocytes under the influence of gamma-interferon and recombinant alpha 2-interferon].

The authors analyze their findings in the study on the effects of interferon preparations (immune gamma-interferon and recombinant alpha 2-interferon) on the ability of blood lymphocytes of dermatoses patients and normal subjects to enter the rosette formation. Preliminary cell treatment with gamma-interferon in vitro essentially influences lymphocytic rosette forming activity, the initial functional activity of cellular receptor system being of paramount importance here. gamma-interferon increased cellular rosette-forming activity and virtually did not influence the unchanged parameters in the patients with lowered values by spontaneous and early active E-RFC. Besides that immune interferon increased the count of 'heavy' rosettes detectable in spontaneous and active E-rosette formation. Recombinant alpha 2-interferon did not essentially alter the blood lymphocyte receptor system.

Adjuvants, Immunologic↗
PubMed1991

Effects of interferons on cultured human melanocytes in vitro: interferon-beta but not-alpha or -gamma inhibit proliferation and all interferons significantly modulate the cell phenotype.

The effects of human recombinant interferon-alpha-2a (rIFN-alpha), natural interferon-beta (nIFN-beta) and recombinant interferon-gamma (rIFN-gamma) on the proliferation, morphology and antigen expression of cultured human melanocytes were studied in vitro. The investigations were performed in 12-O-tetradecanoylphorbol-13-acetate (TPA)- and serum-containing melanocyte growth medium (MGM), in TPA- and serum-free complete melanocyte medium (CMM) and its mitogen reduced variant (RMM). In MGM, none of these interferons inhibited the growth of normal melanocytes at concentrations 1-10,000 international units (IU)/ml over a period of 5 d. Only nIFN-beta, dose dependently, inhibited melanocyte proliferation in CMM and RMM in a 6- and 12-d assay (growth inhibition at 10,000 IU/ml; 77-80% of the controls, p less than 0.001). In contrast, rIFN-alpha and rIFN-gamma exerted no (RMM), or minor effects (CMM) on melanocyte proliferation (only in 12-d assays at 10,000 IU/ml: 24% and 21% of the controls respectively, p less than 0.01). In parallel experiments performed on melanoma cells, all three interferons were potent inhibitors of proliferation in a 5-d serum-free assay (growth inhibition at 10,000 IU/ml; rIFN-alpha 59%, nIFN-beta 78%, rIFN-gamma 56%, all p less than 0.001). In addition, nIFN-beta and also rIFN-gamma caused striking morphologic changes of normal melanocytes in vitro. Especially under greater than or equal to 10 IU/ml rIFN-gamma cytoplasmic spreading and flattening of the cultured melanocytes and their nuclei were seen, thus resembling melanoma cells in vitro. Untreated human melanocytes grown in MGM showed high expression of the melanoma-associated antigens HMB-45 (95-100%) and K.1.2 (40-100%), whereas the progression marker A.1.43 was present only on less than 5% of the cells. Cultured melanocytes were 95-100% positive for histocompatibility antigen class I (HLA-I), 30-75% were positive for ICAM-1, whereas they were negative for HLA-DR. After treatment with rIFN-alpha, increased expression of HLA-I antigens was found; nIFN-beta and rIFN-gamma decreased the labeling with HMB-45 (75-100%) and with K.1.2 (25-80%), whereby the expression of A.1.43 was found slightly increased (5-15%). The HLA class I antigens were upregulated by both nIFN-beta and rIFN-gamma, nIFN-beta being the most potent agent. Also, both nIFN-beta and rIFN-gamma increased the expression of ICAM-1 (nIFN-beta, 75-90%; rIFN-gamma, 90-95%) and induced de novo expression of HLA-DR antigen (nIFN-beta, 15-20%; rIFN-gamma, 65-95%).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1986

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. V. Comparisons with the action of tumor necrosis factor.

A number of similarities and dissimilarities in the anti-tumor effects of TNF and interferon alpha/beta have been observed in DBA/2 mice injected with Friend erythroleukemia cells (FLC). Mouse TNF exerted marked anti-tumor effects in mice injected either s.c. or i.p. with FLC lines 3C18 or 3 gamma R8 resistant in vitro to the cytotoxic effects of TNF. Likewise, mouse interferon alpha/beta had anti-tumor activity in mice injected with these FLC, resistant to the action of interferon alpha/beta or gamma in vitro. The results of histopathologic examination and 31P nuclear magnetic resonance analyses of 3C18 FLC s.c. tumors injected with TNF resembled the results previously obtained for 3C18 FLC tumors injected with interferon alpha/beta, although the effects of TNF occurred more rapidly. Injection of mice with antibody to mouse interferon alpha/beta or gamma did not abrogate the anti-tumor effects of TNF in mice injected i.p. with FLC. Our results suggest that in this experimental system the anti-tumor effects of TNF, like interferon alpha/beta, do not result from a direct effect on the tumor cells themselves but are host-mediated.

Animals↗
PubMed1980

Interferon and spontaneous cytotoxicity in man. IV. Evidence for interferon as the factor in human interferon preparations causing enhancement of spontaneous cytotoxicity.

Human interferon preparations of varying degrees of purity derived from leukocytes, fibroblasts and lymphoblastoid cells all enhanced the spontaneous cytotoxicity of human peripheral lymphocytes, while mouse interferon and human mock interferon preparations did not exert this effect. Fibroblast interferon purified to homogeneity with regard to molecular weight also increased the spontaneous cytotoxicity of lymphocytes. These results indicate that the factor in interferon preparations responsible for the enhancement of spontaneous cytotoxicity is interferon itself.

Cytotoxicity, Immunologic↗
PubMed1985

The synergistic influence of human interferon-gamma and interferon-alpha on suppression of hematopoietic progenitor cells is additive with the enhanced sensitivity of these cells to inhibition by interferons at low oxygen tension in vitro.

The influences of human interferons--natural gamma (2 X 10(7) NIH reference U/mg), recombinant gamma (approximately 5 X 10(6) U/mg), natural alpha (1.4 X 10(8) international reference U/mg), and natural beta (10(6) international reference U/mg)--were evaluated alone or in combination for their effects in vitro on colony formation by low density human bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells incubated at 5% CO2 in normal incubator (approximately 20%) O2 tension or low (5%) O2 tension. Alone, these interferons demonstrated the same dose response inhibitory curves, as we reported previously, when cells were grown at 20% O2. Recombinant IFN-gamma gave the same dose response curve as natural IFN-gamma. Natural or recombinant interferon synergized with IFN-alpha to suppress colony formation at concentrations that were approximately 2 log units lower than that required by either interferon alone. Equal concentrations of these interferons were not needed for the synergistic effect and were still apparent when one was present at concentrations of 2 log units less than the other. IFN-gamma synergized to a lesser extent with IFN-beta, but IFN-alpha did not synergize with IFN-beta. Cells grown at 5% O2 were more sensitive to inhibition by 2 log units less IFN-gamma or IFN-alpha, and this effect was additive with the synergistic effects of IFN-gamma and IFN-alpha together. These results may have physiological, pathological, and/or clinical relevance.

Bone Marrow Cells↗
PubMed1993

Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription.

We previously isolated a cDNA clone encoding interferon consensus sequence-binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, that binds to the interferon (IFN)-stimulated response element (ISRE) of many IFN-regulated genes. In this investigation, we studied the functional role of ICSBP by transient cotransfection of ICSBP cDNA with IFN-responsive reporter genes into the human embryonal carcinoma cell line N-Tera2. These cells were shown not to express ICSBP or IRF-2, thus allowing functional analysis of transfected cDNAs. Cotransfection of ICSBP into cells treated with retinoic acid or any of the IFNs (alpha, beta, or gamma) repressed expression of a chloramphenicol acetyltransferase reporter driven by the major histocompatibility complex class I gene promoter. Similarly, ICSBP repressed expression of chloramphenicol acetyltransferase reporters driven by the ISREs of the 2'-5' oligoadenylate synthetase, guanylate-binding protein, and ISG-15 genes in IFN-treated cells. The repression was dependent on the presence of the ISRE in the reporter. Deletion analysis showed that the putative N-terminal DNA binding domain of ICSBP by itself is capable of mediating the repression. Using the same cotransfection conditions as for ICSBP, a similar repression of these reporters was observed with IRF-2. Finally, ICSBP repressed the IRF-1-mediated induction of major histocompatibility complex class I and IFN-beta reporters in the absence of IFN or retinoic acid. Taken together, these results suggest that ICSBP is a negative regulatory factor capable of repressing transcription of target genes induced by IFN, retinoic acid, or IRF-1.

Base Sequence↗
PubMed1990

Effects of combinations of interferon-beta ser and interferon-gamma on interferon-inducible proteins and on the cell cycle.

SKCO 1 human colon carcinoma cells have been shown to be synergistically inhibited in their growth by the combinations of alpha-interferon (IFN-alpha) or beta-interferon (IFN-beta ser) and gamma-interferon (IFN-gamma). To determine if a correlation could be established between this synergistic antiproliferative effect and a synergistic induction in IFN-inducible proteins, or a unique perturbation in the cell cycle, we studied the effects of IFN-beta ser and IFN-gamma, alone and in combination, on 2',5'-oligoadenylate (2-5A) synthetase, indoleamine-2,3-dioxygenase (IDO), a human analogue of the murine Mx protein (p78), and the phases of cell cycle. 2-5A synthetase was maximally induced after a 24-h exposure to both IFN-beta and IFN-gamma. A synergistic enhancement of 2-5A synthetase activity was observed only with low concentrations of each IFN (0.05 ng/ml). IDO activity was induced by IFN-gamma and the combination of IFN-beta ser and IFN-gamma, but not IFN-beta ser alone. The differences in IDO activity between IFN-gamma and the combination, however, were not statistically significant. The p78 protein was induced in a dose-dependent manner by IFN-alpha and IFN-beta ser. IFN-gamma enhanced the expression of p78 induction by IFN-alpha or IFN-beta ser, even at concentrations of IFN-gamma that did not induce the protein when administered as a single agent. The combination of IFN-alpha and IFN-beta ser, which results in an antagonistic antiproliferative effect, also resulted in an antagonistic induction of p78. No changes in the cell cycle were observed following exposure to IFN-beta ser, IFN-gamma, or the combination, and treatment with IFN-gamma did not inhibit the accumulation of cells in G2M caused by colchicine. Thus, the synergistic antiproliferative effect produced by IFN-beta ser and IFN-gamma in SKCO 1 cells could not be correlated with a synergistic enhancement in 2-5A synthetase or IDO activity, or with a perturbation in the cell cycle. In contrast, the combination of IFN-gamma and IFN-alpha or IFN-beta ser synergistically enhanced the expression of p78 protein in these cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1987

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. VI. Adjuvant therapy after surgery in the inhibition of liver and spleen metastases.

Adult DBA/2 mice were injected s.c. with the highly malignant, interferon-resistant 3C18 line of Friend erythroleukemia cells (FLC). Eight or 9 days after established s.c. tumors had developed, the primary tumor was excised and mice were treated i.p. with either mouse interferon alpha/beta or a control preparation. At the time of surgery, mice already had tumor cells in the liver. All control-treated mice died in the ensuing 2 weeks with extensive tumor metastases in the liver and spleen. Interferon treatment resulted in an inhibition of the development of liver and spleen metastases and a markedly increased survival time. We conclude that interferon alpha/beta is effective as adjuvant therapy after surgery for metastatic disease in mice.

Animals↗
PubMed1983

Human interferon-gamma enhances the expression of class I and class II major histocompatibility complex products in neoplastic cells more effectively than interferon-alpha and interferon-beta.

Human interferon-gamma was more effective than interferon-beta or -alpha in stimulating production of immunoassociated antigens; HLA-A, -B, and -C; and beta(2)-microglobulin in human M14 and Namalva cells. The comparison was made on the basis of antiviral units, and the stimulation could be abolished by treatment of the interferon-gamma preparation with pH 2 or anti-interferon-gamma serum.

Animals↗
PubMed1990

Modulation of interferon receptor expression during combination beta ser-interferon and gamma-interferon treatment of human colon carcinoma cells.

Combination treatment of SKCO1 human colon carcinoma cells with beta ser-interferon (IFN-beta ser) and gamma-interferon (IFN-gamma) results in a synergistic antiproliferative effect. The role of IFN-beta ser and IFN-gamma receptor modulation was investigated as a possible mechanism for this response. IFN-gamma (0.05-50 ng/ml) pretreatment of SKCO1 cells for 24 h decreased specific binding of 125I-IFN-beta ser by 35-60%. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN-gamma showed that this reduction in binding was due to a decreased receptor affinity (control cells, Kd = 46 +/- 1.6 pM; IFN-gamma-treated cells, Kd = 106 +/- 6 pM, n = 2) rather than a significant change in receptor number (receptor number/control cell = 1214 +/- 471, receptor number/IFN-gamma treated cell = 1118 +/- 153, n = 2). In contrast, pretreatment of SKCO1 cells with IFN-beta ser (5 ng/ml) resulted in slight (10-35%) increases in 125I-IFN-gamma-specific binding. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN-beta ser showed a decrease in binding affinity (control cells, Kd = 28 +/- 7 pM; IFN-beta ser-treated cells, Kd = 38 +/- 7 pM, n = 2) and a 32% increase in IFN-gamma receptor sites (receptor number/control cell = 4257 +/- 464, receptor number/IFN-beta ser-treated cell = 5570 +/- 730; n = 2). 125I-IFN-gamma internalization studies performed at 37 degrees C confirmed the cell surface binding assays; IFN-beta ser-treated cells internalized 30-50% more labeled IFN-gamma than untreated cells. However, it is unlikely that differences in binding and internalization of this magnitude play a primary role in the synergistic antiproliferative effect of IFN-gamma with IFN-beta ser in SKCO1 cells. Biochemical modulation at sites distal to the ligand receptor interaction should be investigated.

Cell Division↗
PubMed1984

Potentiating effect of murine interferon-gamma-containing lymphokine preparations on the antiviral and antiproliferative effects of murine interferon-alpha/beta: identification of the potentiation factor as murine interferon-gamma itself.

Mixed preparations of murine interferon-gamma (MuIFN-gamma) and murine interferon-alpha/beta (MuIFN-alpha/beta) have been shown to induce more than additive levels of antiviral protection, when compared to those induced by these interferons given separately. MuIFN-gamma preparations contain many lymphokines and several of these as well as MuIFN-gamma itself may participate in this potentiation. In the present study, natural as well as three recombinant DNA-derived MuIFN-gamma's, in combination with antibody to MuIFN-gamma have been employed to examine the precise role of MuIFN-gamma. The antiviral effect was examined with a single cycle virus yield reduction assay and the antiproliferative effect with a colony formation inhibition assay. Recombinant DNA-derived MuIFN-gamma was as effective as natural MuIFN-gamma at participating in the potentiation of both the antiviral and antiproliferative activities. Antibody to MuIFN-gamma effectively blocked the potentiation of both the antiviral and the antiproliferative activities of natural and recombinant DNA-derived MuIFN-gamma's. Since the recombinant DNA-derived preparations from E. colie can be assumed not to contain mammalian proteins other than MuIFN-gamma, the data conclusively demonstrate that the potentiation factor in MuIFN-gamma preparations is MuIFN-gamma itself.

Animals↗
PubMed1983

A new mass-spectrometric C-terminal sequencing technique finds a similarity between gamma-interferon and alpha 2-interferon and identifies a proteolytically clipped gamma-interferon that retains full antiviral activity.

A novel mass-spectrometric technique is described that permits the identification of the C-terminal peptide of a protein. The technique involves the incorporation of 18O into all alpha-carboxy groups liberated during enzyme-catalysed partial hydrolysis of the protein, followed by mass spectrometry to identify as the C-terminal peptide the only peptide that did not incorporate any 18O. The technique has been used to identify the true C-terminal tryptic peptide of a bacterially produced gamma-interferon and to distinguish it from a peptide produced by anomalous tryptic cleavage. It was found that a closely similar sequence segment of bacterially produced alpha 2-interferon undergoes an analogous cleavage. The technique was also used to identify the C-terminus of a clipped gamma-interferon that retains full antiviral activity.

Amino Acid Sequence↗
PubMed1993

Role of the nitric oxide synthase pathway in inhibition of growth of interferon-sensitive and interferon-resistant Rickettsia prowazekii strains in L929 cells treated with tumor necrosis factor alpha and gamma interferon.

The ability of tumor necrosis factor alpha (TNF-alpha) alone and in combination with gamma interferon (IFN-gamma) to inhibit the growth of interferon-sensitive and -resistant Rickettsia prowazekii strains in mouse L929 cells was examined, and the possible role of the nitric oxide synthase pathway in the suppression of rickettsial growth induced by TNF-alpha, IFN-gamma, or both cytokines was evaluated. TNF-alpha inhibited the growth of strains Madrid E (IFN-gamma sensitive and alpha/beta interferon [IFN-alpha/beta] sensitive) and Breinl (IFN-gamma sensitive and IFN-alpha/beta resistant), but not that of strain 83-2P (IFN-gamma resistant and IFN-alpha/beta resistant), in L929 cells. Inhibition of the growth of the Madrid E strain in L929 cells treated with TNF-alpha and IFN-gamma in combination was greater than that observed with either TNF-alpha or IFN-gamma alone. Similarly, inhibition of the growth of the Breinl strain in L929 cells treated with both cytokines was greater than that observed with TNF-alpha alone; however, it did not differ significantly from the inhibition observed with IFN-gamma alone. Although strain 83-2P was resistant to TNF-alpha or IFN-gamma alone, its growth was inhibited in L929 cells treated with TNF-alpha and IFN-gamma in combination. Nitrite production was measured in mock-infected and infected L929 cell cultures, and the nitric oxide synthase inhibitors NG-methyl-L-arginine (NGMA) and aminoguanidine were used to evaluate the role of the nitric oxide synthase pathway in cytokine-induced inhibition of rickettsial growth. Nitrite production was induced in mock-infected or R. prowazekii-infected L929 cell cultures treated with IFN-gamma plus TNF-alpha, but not in mock-infected cultures that were untreated or treated with IFN-gamma or TNF-alpha alone. Nitrite production was also not induced in untreated, R. prowazekii-infected cultures; however, in some instances, it was induced in infected cultures treated with IFN-gamma or TNF-alpha alone. Nitrite production was blocked by NGMA or aminoguanidine, and these compounds markedly relieved the synergistic inhibitory effect of IFN-gamma plus TNF-alpha on the growth of strain 83-2P in L929 cells. In contrast, NGMA did not alleviate the inhibition of the growth of the Madrid E strain in L929 cells treated with IFN-gamma or TNF-alpha alone; however, it slightly and variably relieved the inhibition of the growth of the Madrid E strain in L929 cells treated with IFN-gamma and TNF-alpha in combination.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗
PubMed1990

A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.

Adolescent↗