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PubMed2006

Determination of the human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex.

Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of cancer, hepatitis C, and multiple sclerosis. All type I IFNs bind to a cell surface receptor consisting of two subunits, IFNAR1 and IFNAR2, associating upon binding of interferon. The structure of the extracellular domain of IFNAR2 (R2-EC) was solved recently. Here we study the complex and the binding interface of IFNalpha2 with R2-EC using multidimensional NMR techniques. NMR shows that IFNalpha2 does not undergo significant structural changes upon binding to its receptor, suggesting a lock-and-key mechanism for binding. Cross saturation experiments were used to determine the receptor binding site upon IFNalpha2. The NMR data and previously published mutagenesis data were used to derive a docking model of the complex with an RMSD of 1 Angstrom, and its well-defined orientation between IFNalpha2 and R2-EC and the structural quality greatly improve upon previously suggested models. The relative ligand-receptor orientation is believed to be important for interferon signaling and possibly one of the parameters that distinguish the different IFN I subtypes. This structural information provides important insight into interferon signaling processes and may allow improvement in the development of therapeutically used IFNs and IFN-like molecules.

Amino Acid Sequence↗
PubMed2006

A randomized trial of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin.

BACKGROUND: There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin. AIM: To evaluate efficacy and safety of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in such patients. METHODS: 161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily and amantadine 200 mg/daily for 12 months. RESULTS: At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure. CONCLUSIONS: The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).

Adult↗
PubMed1986

Interferon-induced gene expression in wild-type and interferon-resistant human lymphoblastoid (Daudi) cells.

Interferon-induced gene expression was analyzed in wild-type and interferon-resistant Daudi cells. Two classes of alpha-interferon-induced mRNAs and proteins were observed: those that were similarly induced in both types of cell and those that were induced only in the wild-type cells. Furthermore, the level of c-myc mRNA decreased in the wild-type but not in the resistant cells. This differential control in the wild-type and resistant cells indicates that there must be either functionally distinct alpha-interferon receptors or more than one pathway leading to altered gene expression triggered by a single receptor.

Cell Division↗
PubMed1995

Interferon-gamma-secreting cells in multiple sclerosis patients treated with interferon beta-1b.

Fifteen percent of multiple sclerosis patients about to be treated with interferon beta-1b exhibited elevated numbers of circulating interferon-gamma-secreting cells, defined as a value that exceeded the mean value for healthy controls by more than two standard deviations. Sixty percent of patients receiving the drug exhibited elevated interferon-gamma-secreting cell numbers during their first 2 months of treatment. Values normalized after 3 months. Prednisone treatment during the first month on the drug prevented the interferon-gamma-secreting cell surge.

Adolescent↗
PubMed1999

Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group.

OBJECTIVE: To compare efficacy of interferon beta-1a, 22 microg or 44 microg weekly, with placebo in relapsing MS. BACKGROUND: Uncertainty exists concerning the optimal dose regimen for interferon beta in relapsing-remitting MS. Many patients and physicians prefer the convenience and lesser side effects of an injection given once weekly (qw) as opposed to three times weekly. Pharmacokinetic data and information on biologic markers suggest that this frequency may be suboptimal. METHODS: Randomized, double-blind study of interferon beta-1a 22 microg, 44 microg, or placebo administered by weekly subcutaneous injection for 48 weeks. Proton density (PD)/T2-weighted and T1-weighted-gadolinium MRI scans during 24 weeks of therapy were analyzed for the number of combined unique (CU) lesions (primary outcome). Biannual PD/T2 scans were analyzed for T2 activity and burden of disease (BOD). RESULTS: CU lesions at 24 weeks had a median of 0.71/scan with placebo, 0.5/scan with 22 microg (not significant), and 0.33/scan with 44 microg (p = 0.002). T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 microg (p = 0.03), and 1.5/1.0 for 44 microg (p = 0.0005). BOD at 48 weeks showed a median increase of 5.9% for placebo compared with a decrease of 1.4% in the 44 microg group (p = 0.0058) and 2% in the 22 microg group (p = 0.0018). No clinical variable, apart from steroid use in the 44 microg qw group (p = 0.014), showed significance. CONCLUSIONS: These data confirm an MRI benefit of interferon beta-1a at low dose in MS, but highlight the limited clinical effect. Taken together with other studies, the data demonstrate a dose-effect relationship for both clinical and MRI variables.

Adjuvants, Immunologic↗
PubMed2002

Incidence of side effects during therapy with different types of alpha interferon: a randomised controlled trial comparing recombinant alpha 2b versus leukocyte interferon in the therapy of naive patients with chronic hepatitis C.

BACKGROUND: Alpha interferon (IFN) alone or in combination with Ribavirin (RBV) is the treatment of choice for HCV related chronic liver disease. There are many types of alpha IFN and to date only few reports are available comparing different types of alpha interferon. We run a randomised controlled trial with the aim to compare tolerability and efficacy of two different types of IFN: recombinant alpha 2b interferon (IFN-R) and leukocyte alpha n-3 interferon (IFN-L) at the same dosage of 3 MU subcutaneously thrice weekly for one year. METHODS: one hundred sixty eight consecutive anti-HCV positive naive patients, 34 mild chronic active hepatitis (MCH), 81 moderate-severe hepatitis (MSCR) and 53 active cirrhosis (CIRR) that met the inclusion criteria were enrolled into the study. The diagnosis of HCV chronic liver disease was established by liver biopsy performed on patients with abnormal serum alanine aminotransferase (ALT) value for at least one year. HCV serology: all patients were tested for confirmatory test RIBA II, HCV-RNA, and identification of viral genotype. Patients were randomised to receive either IFN-R or IFN-L. Follow-up continued for at least two years after stopping treatment. RESULTS: no significant differences were observed between the two groups of treatment as far as the incidence of side effects is concerned. Tolerability was good: only 11 in IFN-R and 8 patients IFN-L group respectively had to stop therapy due to side effects. The two types of IFN showed a comparable efficacy: an end of therapy response was observed in 34% of IFN-R and 30% of IFN-L patients; a sustained response was seen in 16% of IFN-R and in 19% of IFN-L patients. CONCLUSIONS: in the treatment of patients with chronic hepatitis C there was no statistically significant difference in tolerability and efficacy between the two IFNs tested.

Antiviral Agents↗
PubMed2004

Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme.

OBJECT: Little is known about the quantitative modulation of major histocompatibility complex (MHC) Class I expression on human gliomas that is effected by interferons; even less is known about the immunogenic peptides that are accommodated in the peptide-binding motifs of MHC Class I alleles in these brain tumors. In this article the authors investigated the ability of interferon (IFN)alpha and IFNgamma to upregulate MHC Class I expression and to modulate acid-eluted Class I-bound peptides on human glioblastoma multiforme (GBM) cells in vitro. METHODS: Early-passage primary human GBM cell cultures and U87MG GBM cells were incubated with varying doses of INFalpha or IFNgamma ranging between 0 and 2000 U/ml. Upregulation of MHC Class I expression was assayed by immunocytochemical analysis, flow cytometry, and Western blot analysis. Modulation of acid-eluted MHC Class I-bound peptides from the IFN-treated GBM cells was examined with the aid of mass spectroscopy. The in vitro expression of the MHC Class I molecule was upregulated by both IFNalpha and IFNgamma in a dose-dependent manner. Interferon-gamma exhibited a more potent effect on MHC Class I upregulation, peaking at 10 U/ml; whereas the effect of IFNalpha was less marked, reaching a plateau at 500 U/ml. In addition, a native peptide eluted from MHC Class I molecules of human GBM cells was identified and found to be consistently upregulated by IFN treatment. CONCLUSIONS: Interferon-alpha and IFN-gamma can significantly upregulate the MHC Class I molecules that are expressed on the cell surface of human GBM cells as well as the potentially immunogenic peptides bound to the MHC. These results may help explain the molecular basis for increased immunogenicity with IFN treatment of human GBMs and might provide added insight into the design of future antitumor vaccines for human brain tumors.

Cell Line, Tumor↗
PubMed2005

High-dose interferon-alpha2b induction therapy in combination with ribavirin for treatment of chronic hepatitis C in patients with non-response or relapse after interferon-alpha monotherapy.

AIM: To evaluate the daily high-dose induction therapy with interferon-alpha2b (IFN-alpha2b) in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on the assumption that the viral burden would decline faster, thus increasing the likelihood of higher response rates in this difficult-to-treat patient group. METHODS: Seventy patients were enrolled in this study. Treatment was started with 10 MU IFN-alpha2b daily for 3 wk, followed by IFN-alpha2b 5 MU/TIW in combination with ribavirin (1 000-1 200 mg/d) for 21 wk. In case of a negative HCV RNA PCR, treatment was continued until wk 48 (IFN-alpha2b 3 MU/TIW+1 000-1 200 mg ribavirin/daily). RESULTS: The dose of IFN-alpha2b or ribavirin was reduced in 16% of patients because of hematologic side effects, and treatment was discontinued in 7% of patients. An early viral response (EVR) was achieved in 60% of patients. Fifty percent of all patients achieved an end-of-treatment response (EOT) and 40% obtained a sustained viral response (SVR). Patients with no response had a significantly lower response rate than those with a former relapse (SVR 30% vs 53%; P = 0.049). Furthermore, lower response rates were observed in patients infected with genotype 1a/b than in patients with non-1-genotype (SVR 28% vs 74%; P = 0.001). As a significant predictive factor for a sustained response, a rapid initial decline of HCV RNA could be identified. No patient achieving a negative HCV-RNA PCR at wk 18 or later eventually eliminated the virus. CONCLUSION: Daily high-dose induction therapy with interferon-alpha2b is well tolerated and effective for the treatment of non-responders and relapsers, when interferon monotherapy fails. A fast decline of viral load during the first 12 wk is strongly associated with a sustained viral response.

Adult↗
PubMed1991

The genes for the trophoblast interferons and the related interferon-alpha II possess distinct 5'-promoter and 3'-flanking sequences.

The genes for trophoblast interferons (IFN) bovine trophoblast protein-1 (bTP-1) and ovine trophoblast protein-1 (oTP-1) are expressed massively in the trophectoderm of preimplantation bovine and ovine concepti during the period of maternal recognition of pregnancy. These 172-amino acid IFN are closely related to the IFN-alpha II, a family of "long" IFN expressed in virus-induced leukocytes. Genomic Southern blotting with a full-length bTP-1 cDNA revealed about 15 genes that bind the probe with varying intensities. By using more specific probes for the 3'-ends of the cDNA, we have shown that only four to five of these represent bTP-1 genes, whereas no more than another four are IFN-alpha II. Genes for bTP-1 and IFN-alpha II, all of which are intronless, have been isolated from bovine genomic libraries, and their nucleotide sequences were compared. Additional bTP-1 genes and two distinct oTP-1 genes have been isolated from bovine and ovine genomic DNA by using the polymerase chain reaction procedure in conjunction with specific 3'- and 5'- primers (derived from the bTP-1 gene sequences determined above). The promoter region up to 100 bases upstream from the transcription start sites of the trophoblast IFN are almost completely conserved across different genes and across species, yet show only limited sequence identity with IFN-alpha II. Two putative binding regions for interferon regulatory factor-1 as well as several GAAANN motifs (where N is any nucleotide) that have been implicated in viral responsiveness of alpha 1- and beta-IFN genes are retained at identical positions in all of the trophoblast genes. Putative interferon regulatory factor-1-binding nucleotide hexamers and GAAANN motifs are also present in the IFN-alpha II genes, but these are organized very differently than in the trophoblast IFN genes. A GAAATG motif is present in IFN-alpha II promoters but is absent in trophoblast IFN genes. Based on the evidence presented, it is proposed that the trophoblast interferons constitute a separate subclass of IFN-alpha distinct from IFN-alpha II and IFN-alpha I.

Animals↗
PubMedDate not supplied

[Changes in the interferon status of patients with viral hepatitis B when genetically engineered alpha 2-interferon is used].

The status of the interferon (IF) system in patients with acute viral hepatitis B (AVHB) was studied, and its importance as a criterion in the evaluation of the effectiveness of interferon therapy was demonstrated. The clinical study of alpha 2-IF was done in 152 patients with AVHB of moderate severity. The preparation was inoculated intramuscularly or intravenously in a dose of 1 X 10(6) IU twice daily for 5-10 days, a course dose being 10,000,000-20,000,000 IU. Considerable disorders in the functioning of the IF system and significant differences in the interferon status of patients in the study and control groups were demonstrated. The influence of alpha 2-IF on the time course of the interferon status depended on the clinical variants of the disease and the time of the preparation administration. The parameters of the IF system correlated with clinical manifestations of the disease and duration of hepatitis B virus persistence in the blood. This made it possible to use them as a criterion in the evaluation of the therapeutic effectiveness of alpha 2-IF.

Acute Disease↗
PubMedDate not supplied

Effects of phenytoin on the production of interferons: differential effects on type I and type II interferons.

The relative effects of treatment with an anticonvulsant, phenytoin, on the production of interferons were determined for both the murine and human systems. Phenytoin treatment was found to have differential effects on the in vitro production of Type I and Type II interferons. Phenytoin had either no effect (HuIFN-alpha) or an enhancing effect (MuIFN-alpha/beta) on the in vitro production of Type I interferons. In contrast, phenytoin pretreatment had an inhibitory effect on the in vitro production of Type II interferons (IFN-gamma) for both the murine and human systems. Phenytoin appeared to exert its inhibitory effect directly on the IFN-gamma-producing cell and was active even when added as late as 6 h after IFN-gamma induction. This inhibition was not related to a toxic effect of the phenytoin and occurred at phenytoin concentrations which were pharmacologically relevant (10-20 micrograms/ml). The effects of phenytoin on the in vivo production of MuIFN-gamma were also examined. In parallel to the in vitro observations, phenytoin treatment of mice significantly reduced the in vivo induction of MuIFN-gamma. The results raise the possibility that phenytoin therapy in humans may significantly affect the production of HuIFN-gamma.

Animals↗
PubMedDate not supplied

[Comparative experimental studies of the combined use of vaccines, interferon and interferon inducers in neurovirus infections].

Comparative investigations of the combined use of vaccines and interferon in tick-borne encephalitis, herpes, and acute encephalomyelitis of man showed that up to 78% of animal protection against 10--50 LD50 of intraperitoneally inoculated viruses could be achieved. Vaccination alone provided up to 56% survival of the infected mice, while administration of interferon subcutaneously or intraperitoneally in a dose of 800 units (53,300 units per 1 kilo body weight) 18--20 hours before virus gave a survival rate of 36%. The use of vaccine in combination with an interferon inducer, phage of f2 RNA, in tick-borne encephalitis gave up to 75% survival of the infected mice. Four hours after administration, interferon could be detected in mouse sera in a concentration up to 640 units/ml which in immune mice accumulated more rapidly and remained at a higher level 18 hours after inoculation of the inducer.

Animals↗
PubMed1986

Human T4+ lymphocytes produce a phagocytosis-inducing factor (PIF) distinct from interferon-alpha and interferon-gamma.

Unstimulated peripheral blood mononuclear cells from patients with angiocentric T cell immunoproliferative disorders and concanavalin A-stimulated normal peripheral blood mononuclear cells secrete a phagocytosis-inducing factor (PIF) that induces a fivefold to 50-fold enhancement of phagocytosis of IgG-coated ox red blood cells by U937 cells. We investigated the identity, production, and mechanism of the action of PIF. PIF activity was demonstrated in supernatants from nine of 44 phytohemagglutinin-stimulated interleukin 2 (IL 2)-dependent T cell lines and clones derived from purified T4+ cells, but was not found in supernatants from 26 lines and clones derived from phytohemagglutinin-stimulated T8+ cells. In addition, PIF was produced by four of four antigen-specific T cell lines and clones after stimulation with the appropriate antigen and antigen-presenting cells, and by HUT-102, a human T cell lymphotropic virus type I-transformed T cell line. PIF from all of these sources caused significant inhibition of U937 proliferation. This proliferation-inhibiting activity co-purified with phagocytosis-enhancing activity in sizing procedures and isoelectric focusing, which yielded an estimated m.w. of 35,000 to 55,000 and an estimated isoelectric point of 5.0 to 6.0 for PIF. In contrast, IL 2, recombinant interferon-alpha, and recombinant interferon-gamma had no effect on phagocytosis by U937 cells, and antibodies to interferon-alpha and interferon-gamma did not block the phagocytosis-inducing activity of PIF-containing supernatants. PIF appears to be a distinct lymphokine produced by a subset of T4+ lymphocytes, possibly those that proliferate in response to antigen. PIF may be important in the induction of erythrophagocytosis, which is associated with certain T cell immunoproliferative disorders.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Effect of alpha 2-interferon on hairy cells and cell lines: a role for type I interferon receptors and RNA synthesis.

The binding of alpha 2-interferon to highly purified plasma membrane proteins of malignant human lymphoid cells was assessed by Western Blotting. The human hairy cell leukemia cell line JOK-1 revealed three major alpha-interferon binding proteins with molecular weights of 120, 100, and 32 kD. Pretreatment of JOK-1 cells with alpha-interferon in vitro results in a disappearance of these proteins, which is in concordance with receptor down-regulation on JOK-1 cells. In a case of T chronic lymphocytic leukemic (CLL), a differential binding pattern of two proteins with 100 and 85 kD was observed, whereas a case of B-CLL did not yield any signal detection. In addition, mononuclear cells from patients with hairy cell leukemia and CLL were found to differ with respect to the in vitro incorporation of nucleic acid precursors. alpha 2-Interferon enhances [3H] uridine incorporation into hairy cells, whereas this phenomenon can be detected in CLL cells only to a much lesser extent.

DNA, Neoplasm↗
PubMed1987

Differential effect of alpha-interferon and gamma-interferon on thromboplastin response in monocytes and endothelial cells.

Recombinant gamma-interferon (r gamma-IFN) has contrasting effects on thromboplastin (TPL) synthesis induced in monocytes (M) and endothelial cells by bacterial lipopolysaccharide (LPS), phorbol ester (TPA), and phytohaemagglutinin (PHA). In human umbilical vein endothelial cells (HUVEC) the induced thromboplastin response was significantly augmented by r gamma-IFN whereas the monocyte response was inhibited. Recombinant alpha-interferon (r alpha-IFN) had no effect on thromboplastin induction in endothelial cells but had a significant inhibitory effect on the TPL response in monocytes when LPS or LPS and cyclosporin A (CS) were used as inducing agents. Cyclosporin A, previously shown to enhance thromboplastin synthesis induced in monocytes, also contributes to a higher level of thromboplastin activity in endothelial cells. Its effect on monocytes was in most cases fully inhibited by r gamma-IFN (and also by r alpha-IFN when tested). gamma-Interferon and alpha-interferon alone had a weak stimulatory effect or none on thromboplastin synthesis in both cell types.

Cyclosporins↗
PubMed1988

Differential in vitro effects of recombinant alpha-interferon and recombinant gamma-interferon alone or in combination on the expression of melanoma-associated surface antigens.

The effect of individual in vitro concentrations of recombinant alpha-interferon species A (rIFN-alpha-A), recombinant gamma-interferon (rIFN gamma), and combinations of both interferons on the expression of melanoma-associated surface antigens p97 and the high molecular weight proteoglycan (HWM-MAA-240K) as detected by monoclonal antibodies (MoAb) 96.5 and ZME 018 respectively, was examined. rIFN-alpha-A at optimal concentrations of 50 and 500 U/ml caused significant (p less than 0.05 and p less than 0.01, respectively) increases in expression of p97 on the melanoma cell line Hs 294t following a 48-h incubation. No change in 96.5 binding was noted with rIFN-alpha-A concentrations up to 1000 U/ml after a 24-h incubation. Likewise, rIFN gamma at an optimal concentration of 500 U/ml enhanced p97 expression slightly at 24 h (p = 0.053) and more significantly by 48 h at concentrations of 50, 500, and 1,000 U/ml (p less than 0.01, p less than 0.05, and p less than 0.025, respectively). In contrast, neither rIFN gamma nor rIFN-alpha-A had an effect on modulation of the HMW-MAA as detected by ZME 018, irrespective of dose or incubation time. Optimal and suboptimal concentrations of rIFN-alpha-A plus rIFN gamma in combination did not significantly enhance expression of either antigen to a greater extent than that observed with optimal concentrations of each IFN alone, despite the fact that the combination had a synergistic anti-proliferative effect. These data demonstrate that the effects of each interferon (IFN) on the expression of melanoma-associated antigens (MAA) are heterogeneous and depend on IFN type and concentration, exposure time, and characteristics of the antigen studied. Moreover, the data regarding combinations of rIFN-alpha-A and rIFN gamma suggest that mechanisms responsible for IFN effects on MAA modulation are independent from its effects on proliferation. These findings may have clinical relevance with respect to trials using combinations of alpha- and/or gamma-IFN plus MoAb in vivo.

Antigens, Neoplasm↗
PubMed1985

[Assessment of the combined effects of mitomycin C with alpha-interferon or gamma-interferon by the clonogenic assay technique].

The combined effects of Mitomycin C (MMC) with alpha-interferon (HLBI) or gamma-interferon (TRP-2), which have become attractive drugs for use as Biological Response Modifiers, were investigated using the human tumor clonogenic assay technique. Tumors in this study were five human tumor xenografts serially transplanted into nude mice (three gastric cancer, two colon cancer). When the survival fraction occurring with the combination was smaller than that obtained by multiplication of the survival fractions occurring with either drug alone, the combined effect was considered to be synergism. Four out of five xenografts (three gastric cancer, one colon cancer) showed synergistic effects for the combination of MMC with alpha-interferon. Although two gastric cancer xenografts showed synergism for the combination of MMC with gamma-interferon, antagonistic effects were observed in one gastric cancer and one colon cancer xenograft.

Animals↗
PubMed1985

The different effects of recombinant human interferon-gamma and recombinant human interferon-beta on the activation of natural killer cells.

Highly purified recombinant human interferon-gamma produced by Escherichia coli (ReIFN-gamma) was examined for ability to stimulate natural killer (NK) cell cytotoxic activity and antibody-dependent cell-mediated cytotoxicity in human peripheral blood lymphocytes (PBLs) in comparison with natural human interferon-gamma (IFN-gamma) and with recombinant human interferon-beta produced by E. coli (ReIFN-beta). The activity of ReIFN-gamma to stimulate NK cell cytotoxicity was about 10 times greater than that of ReIFN-beta and similar to that of IFN-gamma when PBLs were pretreated with each interferon for 16 hr. The effects of ReIFN-gamma were completely neutralized by a rabbit anti-ReIFN-gamma antibody, but not by a rabbit anti-ReIFN-beta. ReIFN-gamma did not show any significant NK-enhancing effect when it was added directly to the killing phase of standard 51Cr-release assay for 4 hr, while ReIFN-beta showed a marked effect. The time course study showed that the NK-activating effect of ReIFN-gamma was not expressed until 2 hr after the start of incubation, while that of ReIFN-beta was expressed rapidly and sufficiently within 15 min. This kinetic difference between ReIFN-gamma and ReIFN-beta was confirmed by an experiment using the Ca2+-pulse method, in which the killing rate in the Ca2+-dependent stage of NK cytolysis was increased by ReIFN-gamma, but only after 6 hr of preincubation, while the effect by ReIFN-beta was expressed rapidly at 30 min. These findings suggest that ReIFN-gamma and ReIFN-beta may stimulate NK cell cytotoxicity through different intracellular events after they bind to their receptors on the surface of NK cells.

Antibodies↗