Biomedical subjects

N Terada

Publications and source records attributed to N Terada.

At least 235 records · Page 13Linked to original sources

PubMed1994

Apoptosis of acinar cells in the pancreas of rats fed on a copper-depleted diet.

Male Fischer 344 rats weighing 80-90 g were fed on a copper-depleted diet supplemented with 0.6% triethylenetetramine tetrahydrochloride (a copper chelator), and the death of pancreatic acinar cells of these rats was investigated morphologically and biochemically. The weight of the pancreas of these rats decreased from 3 weeks after feeding, and concomitantly the percentage of dead acinar cells increased to the maximum in about the 5th week and decreased subsequently. These dead acinar cells showed light microscopic and electron microscopic characteristics of apoptosis. Furthermore, the electrophoretic pattern of DNAs extracted from the pancreas having many dead acinar cells showed a ladder-like distribution, characteristic of apoptosis. The present results indicate that feeding of rats on a copper-depleted diet supplemented with a copper chelator results in apoptosis of acinar cells of the pancreas.

Animals↗

PubMed1994

Erythrocytosis complicated by multiple paraganglioma.

We report the case of a 22-year-old woman with onset of erythrocytosis at the age of 9 years. Endocrinological and radiological examinations revealed an elevated catecholamine level and the presence of multiple abdominal tumors. After the removal of the tumors, the catecholamine level normalized, whereas erythropoietin remained at the same level and erythrocytosis persisted. The tumor lysate contained considerable amounts of catecholamine but not erythropoietin. Moreover, no erythropoietin mRNA was detected in the tumor by in situ hybridization. These data suggest that this paraganglioma did not produce erythropoietin. A review of the literature showed the existence of patients with early-onset erythrocytosis complicated with paraganglioma, whose erythrocytosis was not relieved even after the resection of paraganglioma.

Abdominal Neoplasms↗

PubMed1994

Mode of action of a topical steroid on immediate phase reaction after antigen challenge and nonspecific nasal hyperreactivity in nasal allergy.

This study compared the effects of 2-week administration of a topical steroid (fluticasone propionate [FP] 100 micrograms twice daily) with placebo in 28 patients with perennial nasal allergy who were allergic to house dust and mites in a double-blind randomized study. The number of inflammatory cells and decidual epithelial cells and concentrations of tryptase and eosinophil cationic protein in nasal lavages, and reactivity of the nasal mucosa to histamine and to antigen were investigated. The topical steroid, FP, significantly inhibited all of these assessments. The degree of improvement of nasal reactivity to histamine significantly correlated with the degree of decrease in eosinophil cationic protein levels.

Administration, Topical↗

PubMed1994

Mechanism of eosinophil infiltration in the patient with subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura's disease). Mechanism of eosinophil chemotaxis mediated by candida antigen and IL-5.

Kimura's disease is a chronic granulomatous disease of unknown etiology. Although eosinophilia is one of the characteristic features in this disease, little is known about the mechanism of eosinophilia. In the present study it was demonstrated that interleukin-5 (IL-5) was produced and released from the site of a granuloma and lymph nodes after stimulation with candida antigen. It was also shown that peripheral blood eosinophils from patients with Kimura's disease contained a large proportion of hypodense eosinophils and that their viability was prolonged. These results strongly suggest that locally produced IL-5 induced by candida antigen contributes to the eosinophilia in this disease.

Adult↗

PubMed1994

Effect of psychic stimulation on plasma catecholamine concentrations and nasal patency in patients with nasal allergy.

To compare the degree of sympathoadrenal and nasal vascular response to psychic stimulation between patients with nasal allergy and normal controls, we measured the changes in plasma norepinephrine and epinephrine concentrations and nasal patency elicited by cannulation into the forearm vein and mental arithmetic in 28 patients with nasal allergy and age- and sex-matched normal controls. Ten of the 28 allergy patients had markedly swollen, pale, edematous nasal mucosa and served as a subgroup of nasal allergy patients. Plasma catecholamine levels increased significantly, with a synchronous increase of nasal patency, during stimulation. Among the three groups, no statistical differences were observed in plasma catecholamine levels either at rest or during stimulation. There was no significant difference in extent of increase of nasal patency induced by stimulation in the total group of subjects with nasal allergy compared with normal controls. However, it was significantly smaller in a subgroup of nasal allergy patients having markedly pale, edematous swelling of the nasal mucosa.

Adult↗

PubMed1994

Inhibitory effects of transforming growth factor-beta 1 on androgen-induced development of neonatal mouse seminal vesicles in vitro.

The effects of transforming growth factor-beta 1 (TGF beta 1) on the development of seminal vesicles (SVs) of neonatal mice were investigated in vitro. SVs from 0-day-old male mice were cultured for 2-8 days in serum-free, chemically defined medium with or without 5 alpha-dihydrotestosterone (DHT) at 10(-8) M in the presence or absence of TGF beta 1. Before culture, SVs from 0-day-old mice had no epithelial branches. SVs cultured in medium with DHT formed numerous epithelial branches after day 2 of culture, whereas epithelial branching did not occur in SVs cultured without DHT. The addition of TGF beta 1 (10 ng/ml) to DHT-containing medium almost completely inhibited the formation of epithelial branches. However, the removal of TGF beta 1 from DHT-containing medium on day 2 or 4 of culture initiated the formation of epithelial branches. TGF beta 1 (10 ng/ml) decreased [3H]thymidine labeling indices of both epithelium and mesenchyme of SVs cultured in medium with DHT during 8 days of culture, an effect that was reversed after the removal of TGF beta 1 from the medium on day 2 or 4 of culture. In contrast, TGF beta 1 (10 ng/ml) did not affect the labeling indices of either epithelium or mesenchyme of SVs cultured in medium without DHT. TGF beta 1 (10 ng/ml) also suppressed the normal increase in protein and DNA contents of SVs cultured in medium with DHT, whereas it did not reduce protein or DNA contents of SVs cultured in medium without DHT. The present study indicates that androgen-dependent growth of the SV can be reversibly inhibited by TGF beta 1, whereas androgen-independent growth of the SV is insensitive to TGF beta 1.

Androgens↗

PubMed1994

5 alpha-reductase activity in developing urogenital tracts of fetal and neonatal male mice.

5 alpha-Reductase activity in testes and urogenital tract tissues from male mice at 14.5 days gestation and 0 days of age (birth) was assessed by measurement of metabolites of testosterone released into the medium in a serum-free culture system. In male mice at 14.5 days gestation, the testis and the cranial portion of the urogenital ridge (UGR), which develops into the epididymis, had little 5 alpha-reductase activity. The caudal portion of the UGR, which develops into the seminal vesicle (SV), and the cranial portion of the urogenital sinus (UGS) had 12-fold higher activity than the cranial portion of the UGR. 5 alpha-Reductase activity in the middle portion of UGR was intermediate between that of its cranial and caudal portions. The highest levels of 5 alpha-reductase activity were detected in the caudal portion of UGS, even though this higher value was not significantly different from those in the caudal UGR or the cranial UGS. In 0-day-old male mice, 5 alpha-reductase activity of testis remained low at a level similar to that observed at 14.5 days gestation. The epididymis also exhibited low 5 alpha-reductase activity in 0-day-old mice, even though this activity had increased 2.2-fold relative to that observed in the cranial UGR at 14.5 days gestation. 5 alpha-Reductase activity of the cranial portion of UGS (prostatic rudiment) was relatively high on day 0 and similar to that in the same region at 14.5 days gestation. The SV and bulbourethral gland (BUG) on day 0 had high 5 alpha-reductase activity, which had increased 1.4- and 1.3-fold, respectively, compared to their 14.5 day embryonic anlage, although the increase was not significant. Through examination of 5 alpha-reductase activity regionally in the developing urogenital tract, it is evident that the concept that testosterone is the active androgen during Wolffian development is overly simplified. The present study suggests the importance of spatial/regional factors in Wolffian duct development in regard to the role of dihydrotestosterone. 5 alpha-reductase activity in the caudal Wolffian duct (SV rudiment) equals or exceeds that in the developing prostate, and at birth, dihydrotestosterone production is virtually identical in the SV and prostate. This suggests that 5 alpha-reduced androgens play a prominent role in the development of SV.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1994

Interleukin-5 gene expression in nasal mucosa and changes in amount of interleukin-5 in nasal lavage fluid after antigen challenge.

Eosinophils and their products are known to cause hyperreactivity and swelling of the nasal mucosa in subjects with nasal allergy. Interleukin-5 (IL-5) not only induces differentiation and proliferation of immature eosinophils but also causes mature cells to accumulate and activate. This study shows that IL-5 is actually produced in the human nasal mucosa by antigen challenge, and it further investigates the changes in the amount of IL-5 in nasal lavage fluids after antigen challenge. Expression of mRNA for IL-5 in nasal mucosa was investigated using the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis. Among the 4 subjects with nasal allergy examined in this study, expression of mRNA for IL-5 was observed in 2 prior to antigen challenge; within 6 h after antigen challenge it was seen in 3 subjects. We also found that the amount of IL-5 in the nasal lavage fluids obtained consecutively after antigen challenge increased predominantly in the late phase, and that the number of eosinophils in the IL-5 positive group was significantly higher than that in the IL-5 negative group. These results strongly suggest that IL-5 contributes to the recruitment of eosinophils in the nasal mucosa of the subjects with nasal allergy.

Adolescent↗

PubMed1994

Release from G0/G1 arrest induced by dimethyl sulfoxide in human lymphoid cells: regulation of synthesis and activation of the p33cdk2 and p34cdc2 kinases.

Raji cells, a human Burkitt's lymphoma-derived cell line, will accumulate in a G0-like state upon prolonged (5-6 days) incubation in medium containing 1.5% dimethyl sulfoxide (DMSO). After removal of DMSO, the cells reenter the cell cycle in a synchronous manner and proliferate. After 5.5 days incubation in DMSO, S phase entry occurs at about 21-24 h after release, which is about the length of the first G1 phase of normal human lymphocytes which are stimulated in vitro to enter the cell cycle. The G0-like state of arrested cells and the sequence of events occurring after release from DMSO mimic, in most ways studied, those of normal lymphocytes. Arrested Raji cells lack many cell cycle-regulated molecules, including cyclin A, proliferating cell nuclear antigen, and the p34cdc2 kinase. They contain only hypophosphorylated p110Rb and a low level of enzymatically inactive p33cdk2 kinase. After reentering the cell cycle, a series of events occurred, including phosphorylation of p110Rb and accumulation of the cyclin A and proliferating cell nuclear antigen proteins in mid-G1 and the accumulation of the p33cdk2 and p34cdc2 proteins beginning in late G1, just prior to S-phase entry. Cyclin E levels in Raji cells appeared to be less regulated than in normal cells, with high levels of this protein being present in resting cells and throughout the entire cell cycle. The time courses of activation of the p34cdc2 and p33cdk2 kinases were similar; both became detectable at about 21 h after release and increased greatly in early S.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗

PubMed1994

Membrane skeleton in fresh unfixed erythrocytes as revealed by a rapid-freezing and deep-etching method.

A rapid-freezing and deep-etching method for examining en face the cytoplasmic aspects of unfixed erythrocyte membranes is described, which provides improved resolution. Normal human erythrocytes were centrifuged, washed in a phosphate buffer solution and pelleted. Glass coverslips were coated with 3-aminopropyl triethoxy silane and glutaraldehyde to make erythrocytes stick to them. A drop containing the erythrocyte pellet was sandwiched between 2 coverslips. The attached erythrocytes were slowly split open in the cytosol buffer solution. The specimens on coverslips were rapidly frozen in an isopentane-propane mixture (-193 degrees C), deeply etched and rotary shadowed with platinum and carbon. Filamentous structures were observed to form fine networks on the cytoplasmic side of erythrocyte membranes. The length of the filaments was shorter than that previously reported for glutaraldehyde-fixed filaments. The number of intersections between filaments was increased as compared with the previous data. It is concluded that dense in situ networks of short filaments beneath erythrocyte membranes can be viewed in a relatively intact state by splitting fresh unfixed specimens followed by the rapid-freezing and deep-etching method.

Cytoskeleton↗

PubMed1993

Neuroblastoma sensitivity to growth inhibition by deferrioxamine: evidence for a block in G1 phase of the cell cycle.

Iron (Fe) is known to be necessary for cellular proliferation. Previous studies have suggested that neuroblastoma cells appear to be relatively sensitive to growth inhibition by a specific Fe chelator, deferrioxamine (DFO), in vitro. Also, DFO has been recently used for the treatment of neuroblastoma patients. In this paper we demonstrate that neuroblastoma cell proliferation in vitro is extremely sensitive to inhibition by DFO as compared to another cell line with almost identical growth kinetics. Neuroblastoma cells treated with DFO adapt appropriately to Fe chelation as measured by marked upregulation of transferrin receptor mRNA, increased functional transferrin receptor, and decreased cellular ferritin concentration. Further studies that quantitated cellular incorporation of 59Fe from added transferrin-59Fe in the presence of DFO indicated that neuroblastoma cells were more sensitive to inhibition of Fe incorporation by the chelator as compared to the other cell line. Neuroblastoma cells treated with DFO showed a consistent arrest in the G1 phase of the cell cycle. For cells taken from the "resting" state this block occurred before the vast majority of cells had entered S or G2-M phases of the cell cycle. Further evidence that neuroblastoma cells were arrested before the G1-S interface was provided when cells inhibited by DFO and released into aphidicolin exhibit arrest at the G1-S interface, whereas release from aphidicolin into DFO resulted in entry into S phase. Also, DFO-treated cells exhibited a decrease in both p34cdc2 immunoreactive protein as well as kinase activity. The results of these latter studies strongly indicate evidence for a Fe requirement for malignant cell proliferation before the onset of DNA synthesis. Our results also provide a basis for further studies that will better define a therapeutic approach to patients with neuroblastoma utilizing DFO treatment.

Aphidicolin↗

PubMed1993

Platelet-activating factor triggers the phosphorylation and activation of MAP-2 kinase and S6 peptide kinase activity in human B cell lines.

Platelet activating factor (PAF), a phospholipid mediator produced by a variety of cell types, has potent biological activities in many cellular systems. We report that stimulation of B cell lines with PAF induced tyrosine phosphorylation of a protein, approximately 42 kDa in size. The PAF receptor antagonist WEB 2086 as well as the structural analogue PAF antagonist CV3988 inhibited the response, demonstrating that the tyrosine phosphorylation was attributable to PAF binding to a specific receptor. Immunoblot analysis, using an antibody to microtubule-associated protein-2 kinase, demonstrated the presence of a single protein species in unstimulated cells. PAF treatment induced the appearance of an additional species with a slightly reduced mobility in the gel. This PAF-inducible band had the same mobility on SDS-PAGE gels as the protein that was tyrosine-phosphorylated after PAF stimulation. Tyrosine phosphorylation of the 42-kDa protein was rapid, detectable within 30 s, and evident over a wide range of PAF concentrations (10(-7) to 10(-10) M). Treatment of cells with phorbol myristate acetate induced tyrosine phosphorylation of a protein with the same mobility in SDS-PAGE gels as the protein induced after PAF stimulation. Lysates from PAF-stimulated lymphoblastoid cells exhibited more than twice the ability to phosphorylate myelin basic protein than lysates from untreated cells. In addition, the ribosomal S6 peptide kinase activity (S6PK) was increased after PAF stimulation of the B cells. Taken together, the results suggest that PAF stimulation of B cells induces the tyrosine phosphorylation and activation of microtubule-associated protein-2 kinase.

B-Lymphocytes↗

PubMed1993

Failure of rapamycin to block proliferation once resting cells have entered the cell cycle despite inactivation of p70 S6 kinase.

Rapamycin (RAP) has recently been shown to inhibit the phosphorylation and activity of p70 S6 kinase (p70s6k). In interleukin (IL)-2-induced cell activation of the human IL-2-dependent T-cell line, Kit225, RAP inhibited p70s6k phosphorylation and activation, but not the activation of MAP kinase, p90 S6 kinase (p90rsk), early tyrosine kinases, or the transcription of the c-fos and c-myc genes. Cell cycle progression induced by IL-2 was arrested by RAP prior to p110Rb phosphorylation and the major increase in total RNA synthesis, both of which were initiated around 6 h after addition of IL-2 and 9 h before the beginning of DNA synthesis. Interestingly, RAP could not inhibit DNA synthesis if addition of the drug was delayed for 6 h after addition of IL-2, despite the fact that even at this time, RAP rapidly induced the accumulation of the dephosphorylated form of p70s6k and that p70s6k was inactivated within 1 h of RAP addition. Furthermore, when RAP was added to continuously growing Kit225 cells, cell proliferation was maintained for at least two additional cell cycles, in the absence of apparent p70s6k activity. These results indicate that 1) among the earliest detectable signals after IL-2 treatment, RAP selectively inhibits p70s6k activation, 2) RAP inactivates p70s6k regardless of the stage of the cell cycle in which the drug is added, 3) RAP blocks resting T-cells from entering the cell cycle, but does not directly arrest cell cycle progression once cells have entered the cycle, and 4) inactivation of p70s6k does not cause immediate arrest of cell cycle progression once cells have entered the cycle.

Amino Acid Sequence↗

PubMed1993

Acute infectious mononucleosis stimulates the selective expression/expansion of V beta 6.1-3 and V beta 7 T cells.

Acute infectious mononucleosis (AIM) is caused by the Epstein-Barr virus (EBV) and is characterized by a proliferation of atypical lymphocytes, predominantly CD8+ T cells. Various diseases associated with T-cell activation have been shown to stimulate the selective expansion of certain V beta (variable region of the T-cell receptor beta chain) expressing T-cell populations. The purpose of this investigation was to determine if the proliferation of T cells accompanying AIM is associated with selective expression/expansion of distinct populations of V beta T cells. We determined V beta expression in eight patients with clinical and laboratory evidence of AIM, including an atypical lymphocytosis. Gel electrophoresis and quantitative analysis were performed on cDNA amplified by the polymerase chain reaction (PCR) using different V beta region primers. Gel electrophoresis analysis showed prominent V beta 6.1-3 and V beta 7 bands in all eight patients with AIM but not in the controls. Quantitative PCR analysis showed that the V beta 6.1-3 and V beta 7 mean PCR ratios increased, respectively, from 163.0 +/- 22.5 and 142.3 +/- 5.5 in controls to 339.9 +/- 38.8 (P < .03) and 396.1 +/- 45.6 (P < .01) in the eight patients with AIM. Two of the eight patients who had increased V beta 6.1-3 and V beta 7 expression were retested after clinical resolution of AIM and no longer had evidence of increased V beta 6.1-3 and V beta 7 T-cell expression. AIM is associated with a selective increased expression of V beta 6.1-3 and V beta 7 T cells present at the time of initial clinical symptoms and atypical lymphocytosis. This increased expression resolves following recovery from AIM. This V beta-specific selective expression resembles the super-antigen response seen after staphylococcal toxin stimulation and may be caused by EBV triggering of selective expansion of V beta 6.1-3 and V beta 7 T-cell subsets.

Acute Disease↗

PubMed1993

Effects of pretreatment with androgen or thyroid hormone on androgen-induced proliferation of granular convoluted tubular cells in mouse submandibular glands.

The effects of pretreatment with androgen or thyroid hormone on androgen-induced proliferation of granular convoluted tubular cells (GCT cells) in the submandibular glands of ovariectomized female BALB/c or C57BL/6 mice were investigated. The proliferation of GCT cells was estimated by their labeling index. Daily injections of 5 alpha-dihydrotestosterone (DHT) (100 micrograms/mouse/day) caused a transient increase in the labeling index of GCT cells of ovariectomized 60-day-old BALB/c mice during the first four injections, but injections of thyroxine (T4) (15 micrograms/mouse/day) did not. On the other hand, both DHT and T4 increased the esteroprotease activity, a marker of the differentiation of GCT cells, time dependently. Injections of DHT into ovariectomized 102-day-old BALB/c mice also caused a transient increase in the labeling index of GCT cells. However, pretreatment of ovariectomized 60-day-old BALB/c mice with DHT for 4 or 14 days completely abolished the DHT-induced increase in the labeling index of 102-day-old mice, and pretreatment with T4 for 14 days reduced this increase. Pretreatment with DHT or T4 for 14 days did not affect the DHT-induced increase in esteroprotease activity. Pretreatment of ovariectomized 60-day-old C57BL/6 mice with DHT for 14 days also completely abolished the DHT-induced increase in the labeling index of GCT cells at the age of 102 days, but pretreatment with T4 for 14 days did not affect the increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling.

The high-affinity receptors for granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3) and IL-5 consist of two subunits, alpha and beta. The alpha subunits are specific to each cytokine and the same beta subunit (beta c) is shared by these three receptors. Although none of these receptor subunits has intrinsic kinase activity, these cytokines induce protein tyrosine phosphorylation, activation of Ras, Raf-1 and MAP kinase, and transcriptional activation of nuclear proto-oncogenes such as c-myc, c-fos and c-jun. In this paper, we describe a detailed analysis of the signaling potential of the beta c subunit by using a series of cytoplasmic deletion mutants. The human beta c consists of 881 amino acid residues. A C-terminal deletion mutant of beta c at amino acid 763 (beta 763) induced phosphorylation of Shc and activation of Ras, Raf-1, MAP kinase and p70 S6 kinase, whereas a deletion at amino acid 626 (beta 626) induced none of these effects. The beta 763 mutant, as well as the full-length beta c, induced transcription of c-myc, c-fos and c-jun. Deletions at amino acid 517 (beta 517) and 626 (beta 626) induced c-myc and pim-1, but no induction of c-fos and c-jun was observed. GM-CSF increased phosphatidylinositol 3 kinase (PI3-K) activity in anti-phosphotyrosine immunoprecipitates from cells expressing beta 763 as well as beta c, whereas it was only marginally increased from cells expressing beta 517 or beta 626. Thus, there are at least two distinct regions within the cytoplasmic domain of beta c that are responsible for different signals, i.e. a membrane proximal region of approximately 60 amino acid residues upstream of Glu517 is essential for induction of c-myc and pim-1, and a distal region of approximately 140 amino acid residues (between Leu626 and Ser763) is required for activation of Ras, Raf-1, MAP kinase and p70 S6 kinase, as well as induction of c-fos and c-jun.

Amino Acid Sequence↗

PubMed1993

Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle.

The effects of rapamycin (RAP) on cell cycle progression of human T cells stimulated with PHA were examined. Cell cycle analysis showed that the RNA content of cells stimulated with PHA in the presence of RAP was similar to that of control T cells stimulated with PHA for 12-24 hr in the absence of the drug. This level was substantially higher than that seen in cells stimulated in the presence of cyclosporin A (CsA), an immunosuppressant known to block cell cycle progression at an early point in the cycle. However, the point in the cell cycle at which RAP acted appeared to be well before the G1/S transition, which occurs about 30-36 hr after stimulation with PHA. In an attempt to further localize the point in the cell cycle where arrest occurred, a set of key regulatory events leading to the G1/S boundary were examined, including p110Rb phosphorylation, which occurred at least 6 hr prior to DNA synthesis, p34cdc2 synthesis, and cyclin A synthesis. In control cultures, p110Rb phosphorylation was detected within 24 hr of PHA stimulation; p34cdc2 and cyclin A synthesis were detected within 30 hr. Addition of RAP to the cultures inhibited each of these events. In contrast, early events, including c-fos, IL-2, and IL-4 mRNAs expression, and IL-2 receptor (p55) expression, were only marginally affected, if at all, in PHA-stimulated T cells. Furthermore, the inhibition of cell proliferation by RAP could not be overcome by addition of exogenous IL-2. These results indicate that RAP blocks cell cycle progression of activated T cells after IL-2/IL-2 receptor interaction but prior to p110Rb phosphorylation and other key regulatory events signaling G1/S transition.

Base Sequence↗

PubMed1993

Characterization of the progression signal for human T-cell proliferation provided by monoclonal antibodies to the CD3-TCR complex.

Following T-cell activation, two distinct stages in the proliferative response can be identified. The first stage or state of competence (G0 to G1 transition) is defined by the acquisition of the ability of activated T cells to proliferate in response to growth factors. The second or progression phase relates to the progression of cells to DNA synthesis in response to exogenous growth factors (e.g., IL-2) or inducers of growth factor synthesis (e.g., phorbol esters). In the present manuscript we provide evidence that soluble monoclonal antibodies (mAbs) to CD3 or the T-cell receptor (TCR), similar to the phorbol esters, can induce IL-2 production and cell proliferation in competent but not resting T cells. The data indicate the role of CD3-TCR complex triggering not only as an "activating or competence signal" but demonstrate its capacity to signal in the progression phase as well. However, there were distinct differences when competent T cells were stimulated by phorbol ester compared to soluble antibodies to CD3 or TCR. Antibodies to the CD3-TCR complex, when compared to phorbol ester, induced less proliferation in competent, memory T cells (CD45RO) than in competent, naive T cells (CD45RA). In contrast to phorbol ester, the induction of IL-2 transcription and cell proliferation in competent cells by soluble mAbs BMA 031 (anti-alpha/beta T-cell receptor) or OKT3 (anti-CD3) was inhibited by cyclosporin A (CsA). This implies that in activated T cells there is a step between activation of the CD3-TCR complex and the point(s) of action of phorbol ester that is susceptible to CsA in activated cells. Alternatively, the data may indicate involvement of different regulatory elements with different sensitivities to CsA for the induction of IL-2 transcription by phorbol ester or antibodies to the CD3-TCR complex.

Antibodies, Monoclonal↗