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At least 811 records · Page 45Linked to original sources
PubMed1997

Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair.

Transforming growth factor (TGF)-beta isoforms (TGF-beta 1, -beta 2, and -beta 3) regulate cell growth and differentiation and have critical regulatory roles in the process of tissue repair and remodeling. Signal transduction for TGF-beta function is transmitted by a heteromeric complex of receptors consisting of two serine/threonine kinase transmembrane proteins (RI and RII). We have previously shown that each TGF-beta isoform is widely expressed in a distinct spatial and temporal pattern throughout the processes of excisional and incisional wound repair. As the presence of TGF-beta receptors determines cellular responsiveness, we have currently examined, by immunohistochemistry, the localization of RI (ALK-1, ALK-5) and RII throughout repair of full-thickness excisional wounds up to 21 days after wounding. The expression of RI (ALK-5) and RII co-localized in both the unwounded and wounded skin and was present in the same cell types as TGF-beta ligands. However, immunoreactivity for TGF-beta receptors, throughout repair, occurred 1 to 5 days later than TGF-beta isoform immunostaining. This implies that the presence of TGF-beta ligands may up-regulate TGF-beta receptors for function and/or may reflect a lag due to local processing of latent TGF-beta. As observed for the immunohistochemical localization of TGF-beta isoforms in unwounded skin, RI and RII were expressed throughout the four layers of the epidermis, showing a wavy pattern of slight to moderate immunostaining, and hair follicles, sweat glands, and sebaceous glands were moderately immunoreactive. The extracellular matrix, fibroblasts, and blood vessels in the dermis were not immunoreactive. After injury, as observed for TGF-beta ligands, RI and RII expression was increased in the epidermis adjacent to the wound and the epithelium migrating over the wound was completely devoid of TGF-beta receptor immunoreactivity until re-epithelialization was completed by day 7 after wounding. The dermis was only slightly immunoreactive for RI and RII until day 5 when, immediately under the wound, immunostaining for fibroblasts, connective tissue cells, and newly forming vasculature began to increase and remained intense until day 14. Consistent with the role for TGF-beta in scarring, numerous fibroblasts, ostensibly active in the production of extracellular matrix components, continued to be slightly immunoreactive for RI and RII at 21 days. The ALK-1 (TSR-1) type I receptor, which binds both activin and TGF-beta, showed slight immunostaining early in repair (days 1 to 7) that progressively became more intense later in repair after day 10 and through day 21. This suggests that there may be a switch to a different type I receptor, implying different functions for the ALK-1 and ALK-5 receptors. The concomitant expression of TGF-beta isoforms and their signal-transducing receptors denote potential spatial and temporal activity of TGF-beta. Thus, although TGF-beta ligand is present, TGF-beta would not function in wound repair until a later time when RI and RII appear. This information should aid in the development of receptor antagonists as a therapeutic approach to scarring and fibrosis. In addition, these studies underscore the importance of defining the expression of proteins in vivo to establish a basis for the analysis of mechanisms in vitro.

Animals↗
PubMed1997

Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries.

Transforming growth factor (TGF)-beta has been implicated in the regulation of normal and neoplastic anterior pituitary cell function. TGF-beta regulates the expression of various proteins, including p27Kip1 (p27), a cell cycle inhibitory protein. We examined TGF-beta, TGF-beta type II receptor (TGF-beta-RII), and p27 expression in normal pituitaries, pituitary adenomas, and carcinomas to analyze the possible roles of these proteins in pituitary tumorigenesis. Normal pituitary, pituitary adenomas, and pituitary carcinomas all expressed TGF-beta and TGF-beta-RII immunoreactivity. Reverse transcription polymerase chain reaction analysis showed TGF-beta 1, -beta 2, and -beta 3 isoforms and TGF-beta-RII in normal pituitaries and pituitary adenomas. Pituitary adenomas cells cultured for 7 days in defined media showed a biphasic response to TGF-beta with significant inhibition of follicle-stimulating hormone secretion at higher concentrations (10(-9) mol/L) and stimulation of follicle-stimulating hormone secretion at lower concentrations (10(-13) mol/L) of TGF-beta 1 in gonadotroph adenomas. Immunohistochemical analysis for p27 protein expression showed the highest levels in nontumorous pituitaries with decreased immunoreactivity in adenomas and carcinomas. When nontumorous pituitaries and various adenomas were analyzed for p27 and specific hormone production, growth hormone, luteinizing hormone, and thyroid-stimulating hormone cells and tumors had the highest percentages of cells expressing p27, whereas adrenocorticotrophic hormone cells and tumors had the lowest percentages. Immunoblotting analysis showed that adrenocorticotrophic hormone adenomas also had the lowest levels of p27 protein. Semiquantitative reverse transcription polymerase chain reaction and Northern hybridization analysis did not show significant differences in p27 mRNA expression in the various types of adenomas or in nontumorous pituitaries. In situ hybridization for p27 mRNA showed similar distributions of the gene product in nontumorous pituitaries, pituitary adenomas, and carcinomas. These results indicate that TGF-beta and TGF-beta-RII are widely expressed in nontumorous pituitaries and in pituitary neoplasms and that TGF-beta 1 regulates pituitary hormone secretion. The levels of the TGF-beta-regulated protein p27 decreases in the progression of normal to neoplastic pituitaries. In contrast, the mRNA levels of p27 remained relatively constant in nontumorous pituitaries, pituitary adenomas, and carcinomas, indicating that p27 protein levels in adenomas and carcinomas are regulated by translational and post-translational mechanisms.

Adenoma↗
PubMed1995

Expression of transforming growth factor beta and transforming growth factor beta receptors on AIDS-associated Kaposi's sarcoma.

Several humoral growth factors may contribute to the development and growth of AIDS-associated Kaposi's sarcoma (KS). They are either provided by chronically activated cells of the immune system or in an autocrine/paracrine manner by the neoplastic cells themselves. Transforming growth factor beta(TGF-beta) may directly enhance the growth of KS cells and tumor matrix formation. To mediate a signal both TGF-beta receptors type I and type II (TbetaR-I and TbetaR-II) have to be expressed. We investigated the expression of TGF-beta, TGF-beta receptors types I and II, and endoglin, a nonsignaling-type TbetaR-III, by means of immunohistochemistry on skin biopsies from patients with AIDS-related KS. We found that the TGF-beta ligand was expressed by KS cells in 9 of 11 samples. TbetaR-II was strongly expressed in 10 of 12 samples, but none of the investigated tumor samples stained for TbetaR-I. Endoglin was weakly expressed on all KS lesions and stained the endothelium of tumor-associated vessels in 92% of the samples. These findings show that most KS lesions have the ability to produce TGF-beta and that KS cells maintain a high expression of TbetaR-II in the absence of TbetaR-I, which may allow KS to escape growth inhibitory effects of endocrine or paracrine TGF-beta.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Characterization of a 60-kDa cell surface-associated transforming growth factor-beta binding protein that can interfere with transforming growth factor-beta receptor binding.

We have characterized a 60-kDa transforming growth factor-beta (TGF-beta) binding protein that was originally identified on LNCaP adenocarcinoma prostate cells by affinity cross-linking of cell surface proteins by using 125I-TGF-beta 1. Binding of 125I-TGF-beta 1 to the 60-kDa protein was competed by an excess of unlabeled TGF-beta 1 but not by TGF-beta 2, TGF-beta 3, activin, or osteogenic protein-1 (OP-1), also termed bone morphogenetic protein-7 (BMP-7). In addition, no binding of 125I-TGF-beta 2 and 125I-TGF-beta 3 to the 60-kDa binding protein on LNCaP cells could be demonstrated by using affinity labeling techniques. The 60-kDa TGF-beta binding protein showed no immunoreactivity with antibodies against the known type I and type II receptors for members of the TGF-beta superfamily. Treatment of LNCaP cells with 0.25 M NaCl, 1 microgram/ml heparin, or 10% glycerol caused a release of the 60-kDa protein from the cell surface. In addition, we found that the previously described TGF-beta type IV receptor on GH3 cells, which does not form a heterometric complex with TGF-beta receptors, could be released from the cell surface by these same treatments. This suggests that the 60-kDa protein and the similarly sized TGF-beta type IV receptor are related proteins. The eluted 60-kDa LNCaP protein was shown to interfere with the binding of TGF-beta to the TGF-beta receptors. Thus, the cell surface-associated 60-kDa TGF-beta binding protein may play a role in regulating TGF-beta binding to TGF-beta receptors.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Effect of the interaction between transforming growth factor beta and erythropoietin on the proliferation of normal erythroid progenitors and leukemic UT-7 cells: action of transforming growth factor beta on the erythropoietin receptor.

The actions of transforming growth factor beta (TGF beta) and erythropoietin (Epo) were studied using normal erythroid progenitors from fetal rat liver and spleen at 18, 19 and 20 days. rhTGF beta 1 inhibited the growth of late BFUe colonies significantly at each age and in both organs in methylcellulose cultures containing 2 U/ml rhEpo. There was no significant inhibition of CFUe proliferation, except for spleen CFUe at 18 days, suggesting different CFUe sensitivities to growth factors at a given fetal age, 18 days, in liver and spleen. The colorimetric MTT assay was used to examine the inhibition of the growth of human leukemic UT-7 cells by TGF beta 1. TGF beta 1 inhibited the proliferation of UT-7 cells in cultures without Epo at 24 h and in cultures with Epo at 24 and 72 h. The specific binding of [125I]Epo to UT-7 surface was decreased by TGF beta 1 without any change in non-specific binding. TGF beta 1 also inhibited the expression of Epo-receptors on UT-7 cells, without changing receptor affinity. The inhibition of hematopoietic progenitor cell growth by TGF beta could involve altering the cell surface expression of growth factor receptors.

Animals↗
PubMed2000

Drug penetration as studied by noninvasive methods: fourier transform infrared-attenuated total reflection, fourier transform infrared, and ultraviolet photoacoustic spectroscopy.

The penetration of the drugs dithranol and methoxsalen from semisolid Vaseline formulation into an artificial dodecanol-collodion membrane was followed by three spectroscopic methods; they are, step-scan Fourier transform infrared (FTIR) photoacoustic spectroscopy (PAS) with phase modulation, FTIR-attenuated total reflection (FTIR-ATR), and ultraviolet (UV) PAS. The uptake of the drug in the membrane was quantified by monitoring the dependence of an appropriate drug band on the penetration time. The PAS experiments were carried out with various modulation frequencies for generating various sampling depths. Based on Fick's second law, the diffusion coefficient was derived by numerical fitting of the experimental data. It appears that the diffusion coefficient for the drug in the membrane depends on the distance. The comparative studies demonstrate that FTIR-ATR is favored for permeation studies, whereas the PAS techniques are capable of providing the drug penetration profile in the membrane. Thus, extended experimental data are available for new insight into the penetration process. However, because of the photacoustic cells at hand, PAS is only suitable for in vitro studies.

Administration, Topical↗
PubMed1977

In vivo leukemic transformation: cytogenetic evidence of in vivo leukemic transformation of engrafted marrow cells.

A 4-year-old girl with acute myeloblastic leukemia was treated with 50 mg/kg cyclophosphamide daily for 4 days before being given 1.7 X 10(8) bone marrow cells/kg from her HL-A identical, MLC nonreactive, cytogenetically normal brother. The patient died 92 weeks after the marrow graft. Postmortem examination showed increased myeloblasts and promyelocytes. Cytogenetic studies before transplantation showed that all sex determination metaphases had an XX pattern, and 41% of the hyperdiploid metaphases had an additional 19-20(F) chromosome. At autopsy all hyperdiploid metaphases with XY pattern and 43% of the hyperdiploid metaphases with an XX pattern had an additional F chromosome. Occasional metaphases with 47, XX, + F or 47, XY, + F were seen during the follow-up studies. These findings indicated that an acute leukemia had developed in the XY cell line of this artifically induced sex chimeric child. This suggests that a leukemic stimulus other than that proposed to be induced by total-body irradiation existed in this patient and transformed the engrafted cells.

Bone Marrow↗
PubMed1983

Morphologic and mitogenic responses of rabbit synovial fibroblasts to transforming growth factor beta require transforming growth factor alpha or epidermal growth factor.

We tested the hypothesis that normal synovial fibroblasts might proliferate in response to transforming growth factors (TGFs), peptides that are extracted with acid-ethanol from bovine kidney or salivary gland and that cause anchorage-independent growth of normal cells. A 72-hour exposure of confluent monolayers of rabbit synovial fibroblasts in 10% fetal calf serum to partially purified TGF-beta in the presence of TGF-alpha gave a 2- to 5-fold increase in incorporation of 3H-thymidine, protein content, and cell number. Similar results were obtained with high pressure liquid chromatography-purified TGF-beta in the presence of epidermal growth factor (EGF) (a type of TGF-alpha). By itself, purified TGF-beta was not mitogenic; it depended absolutely on EGF. However, only TGF-beta along with EGF, and not EGF alone, induced a marked morphologic change: a piling up of cells into foci resembling those commonly seen in primary cultures of rheumatoid synovial cells. Mitogenic responses induced by the TGF-beta-EGF combination were prevented by all-trans-retinoic acid but not by indomethacin or dexamethasone. The data indicate that TGF-beta, a peptide extracted from normal cells, can act in concert with EGF to cause proliferation and piling up of synovial cells and raise the possibility that these factors may play a role in rheumatoid arthritis and other proliferative but nonmalignant diseases as well.

Animals↗
PubMed2005

Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts.

OBJECTIVE: To confirm the involvement of alphavbeta5 in the self-activation system in systemic sclerosis (SSc) fibroblasts. METHODS: Levels of alphavbeta5 expression were analyzed by immunoprecipitation. The promoter activity of the human alpha2(I) collagen gene was determined by transient transfection assay. Phosphorylation levels and DNA binding ability of Smad3 were investigated by immunoprecipitation and DNA affinity precipitation, respectively. The localization of active transforming growth factor beta (TGFbeta) was determined by coculture assay using TMLC cells (mink lung epithelial reporter cells that stably express a portion of the plasminogen activator inhibitor 1 promoter). The morphologic features of cells were determined by immunofluorescence analysis. RESULTS: Levels of alphavbeta5 expression were significantly elevated in SSc fibroblasts compared with normal fibroblasts. Treatment with anti-alphavbeta5 antibody or beta5 antisense oligonucleotide significantly reduced human alpha2(I) collagen gene promoter activity in SSc fibroblasts. In SSc fibroblasts pretreated with TGFbeta1 antisense oligonucleotide, the exogenous latent TGFbeta1 stimulation significantly increased human alpha2(I) collagen gene promoter activity; this effect was significantly reduced in the presence of anti-alphavbeta5 antibody. Phosphorylation levels and DNA binding ability of Smad3 in SSc fibroblasts were significantly reduced by treatment with beta5 antisense oligonucleotide. The luciferase activity of TMLC cells cocultured with SSc fibroblasts was significantly elevated compared with that of TMLC cells cocultured with normal fibroblasts and was significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of SSc fibroblasts. CONCLUSION: Up-regulated expression of alphavbeta5 contributes to the establishment of autocrine TGFbeta signaling in SSc fibroblasts through activation of endogenous latent TGFbeta1.

Antibodies, Blocking↗
PubMed1995

Transforming growth factor-beta inhibits interleukin-12-induced production of interferon-gamma by natural killer cells: a role for transforming growth factor-beta in the regulation of T cell-independent resistance to Toxoplasma gondii.

Severe-combined immune deficient (SCID) mice have been found to resist infection with the intracellular protozoan parasite Toxoplasma gondii via interleukin (IL)-12 stimulation of interferon (IFN)-gamma production by natural killer (NK) cells. Previously, we demonstrated the presence of increased levels of transcripts for transforming growth factor-beta (TGF-beta) in the brains and lungs of SCID mice infected with T. gondii, leading us to investigate the role of TGF-beta in the mechanism of resistance to T. gondii in these mice. Stimulation of splenocytes from SCID mice with heat-killed T. gondii resulted in production of low levels of IFN-gamma and a two to threefold increase in levels of TGF-beta in the culture supernatants. Production of IFN-gamma in these cultures was increased three to fourfold by addition of anti-TGF-beta antibody. Stimulation of splenocytes from SCID mice with IL-12 in combination with either TNF-alpha or IL-1 beta resulted in production of high levels of IFN-gamma. Addition of TGF-beta to these cultures inhibited production of IFN-gamma in a dose-dependent manner. Immunohistochemical studies revealed increased levels of TGF-beta protein in the spleens of SCID mice 5 days after oral infection with the ME49 strain of T gondii, and brains of SCID mice at 18 days post-infection. However, no difference was detected in the levels of TGF-beta transcripts in the spleens of uninfected mice or mice infected for 5 days. To test whether TGF-beta could antagonize IL-12 mediated resistance to T. gondii in vivo, we administered TGF-beta to SCID mice infected with T. gondii. This treatment resulted in earlier mortality of infected mice and significantly reduced the ability of exogenous IL-12 to delay time-to-death. Administration of anti-TGF-beta to SCID mice, beginning 24 h prior to infection and every 2 days thereafter, delayed significantly time-to-death. Together, our data demonstrate that TGF-beta antagonizes the ability of IL-12 to stimulate production of IFN-gamma by splenocytes from SCID mice, and suggest a role for TGF-beta in regulation of T cell-independent resistance to T. gondii.

Animals↗
PubMedDate not supplied

Impact of transforming viruses on cellular mutagenesis, genome stability, and cellular transformation.

It is estimated that 15% of all cancers are etiologically linked to viral infection. Specific cancers including adult T-cell leukemia, hepatocellular carcinoma, and uterine cervical cancer are associated with infection by human T-cell leukemia virus type I, hepatitis B virus, and high-risk human papilloma virus, respectively. In these cancers, genomic instability, a hallmark of multistep cancers, has been explicitly linked to the expression of oncoproteins encoded by these viruses. This review discusses mechanisms utilized by these viral oncoproteins, Tax, HBx, and E6/E7, to mediate genomic instability and cellular transformation.

Cell Cycle↗
PubMed1998

Levels of transforming growth factor beta and transforming growth factor beta receptors in rat liver during growth, regression by apoptosis and neoplasia.

Transforming growth factor beta1 (TGF-beta1) has been implicated as inhibitor of cell proliferation and a potent inducer of apoptosis in vitro and in vivo after the administration of high doses. To assess the role of endogenous TGF-beta1, we quantitated the cytokine and its receptors in rat liver during regenerative and hyperplastic growth, regression by apoptosis, and in hepatocellular carcinoma (HCC). This was accomplished by Northern blot analysis and by RNase protection assay of the messenger RNA (mRNA) of TGF-beta1 and TGF-beta receptors (TbetaR) types I to III and by an activity bioassay of the TGF-beta proteins. Untreated rat livers were found to contain 15.6 +/- 4.8 ng TGF-beta1 protein/g tissue; TGF-beta2 protein was not detected. To induce toxic cell death and subsequent regenerative DNA synthesis in the liver, rats were treated with a necrogenic dose of carbon tetrachloride (CCl4). After 24 and 48 hours, there was an upregulation of TGF-beta1 (mRNA, up to tenfold; protein, about twofold) and of TbetaRs (mRNA: two- to fourfold); that indicates an overall enhanced production of and sensitivity to TGF-beta1, which may serve to confine the regenerative response. Hyperplastic liver growth and regression of the hyperplasia were induced by treatment with cyproterone acetate (CPA) or nafenopin (NAF) followed by withdrawal; neither mRNAs of TGF-beta1 and TbetaR types I to III nor TGF-beta1 protein exhibited significant changes during the growth phase or during regression by apoptosis. We also studied neoplastic growth. HCC, obtained after long-term treatment with NAF, exhibited high rates of cell replication and apoptosis. The majority of lesions contained mRNA and protein of TGF-beta1 and mRNA of TbetaR types I to III at concentrations similar to those of the surrounding tissue. In conclusion, during liver regeneration there is a pronounced upregulation of expression of both TGF-beta1 and TbetaRs I to III, but not during mitogen-induced liver growth or regression. It appears that apoptosis is induced via altered local concentration of TGF-beta1, in a paracrine and/or autocrine way. By this mechanism the lethal effects of TGF-beta1 may be locally confined, and overshoots of apoptosis in the liver may be prevented.

Animals↗
PubMed1989

Modulation of transforming growth factor alpha-dependent expression of epidermal growth factor receptor gene by transforming growth factor beta, triiodothyronine, and retinoic acid.

We have investigated the actions of transforming growth factor (TGF) type alpha on epidermal growth factor (EGF) receptor mRNA expression in MDA-468 human mammary carcinoma cells in serum-free media. We found that exposure of MDA-468 cells to TGF alpha results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGF beta 1 enhanced the accumulation of EGF receptor mRNA induced by TGF alpha in a time- and dose-dependent manner. We also found that triiodothyronine at physiological concentrations exerts synergistic control on the action of TGF alpha alone, or in association with TGF beta 1, on EGF receptor mRNA expression. Similarly, retinoic acid treatment also enhanced in a time- and dose-dependent manner the TGF alpha-dependent response of EGF receptor mRNA and acted synergistically with TGF beta 1. The results described here suggest that optimum regulation of EGF receptor gene expression by TGF alpha is a complex process involving synergistic interactions with heterologous growth factors and hormones.

Breast Neoplasms↗
PubMed1994

The role of cysteine-949 in the binding of transforming growth factor-beta 1 and transforming growth factor-beta 2 to alpha 2-macroglobulin.

The reaction of alpha 2-macroglobulin (alpha 2M) with proteinases or methylamine causes a major conformational change in alpha 2M and cleavage of the alpha 2M thiol ester bonds. The resulting free Cys residues (Cys-949) contain the only free thiol groups in alpha 2M. In this investigation, we explored the role of Cys-949 in the binding of transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 2 to alpha 2M-methylamine. Modification of preformed alpha 2M-methylamine with iodoacetamide did not change the binding affinity of alpha 2M-methylamine for TGF-beta 1 or TGF-beta 2; the apparent KD values were 82 nM and 10 nM, respectively. TGF-beta binding also remained unchanged when tested using an alpha 2M derivative prepared by simultaneous treatment of alpha 2M with methylamine and iodoacetamide. The slow thiol-disulfide exchange reaction that irreversibly stabilizes noncovalent growth factor-alpha 2M-methylamine complexes was completely inhibited by modification of Cys-949. These studies demonstrate that Cys-949 in alpha 2M is not essential for binding of TGF-beta 1 and TGF-beta 2 noncovalently; however, this residue plays a critical role in the covalent stabilization step of the reaction mechanism.

Cysteine↗
PubMed1998

Suppression of transformed phenotypes of Ha-ras-transformed NIH3T3 cells by caspase-2.

Biological effects of caspases-1, -2 and -3 have been investigated by transfection of these human cDNAs into activated c-Ha-ras-transformed NIH3T3 mouse fibroblasts. High expression of caspase-2 but not caspase-1 or -3 induced flat revertant cells which lost the ability of anchorage-independent growth. Notably, these revertants contained a reduced amount of Ras protein. These suggest that caspase-2 exhibited a tumor-suppressive activity by affecting the expression level of Ras protein.

3T3 Cells↗
PubMed1997

Transformation-related expression of a low-molecular-mass tropomyosin isoform TM5/TM30nm in transformed rat fibroblastic cell lines.

We cloned a full-length rat TM5/TM30nm cDNA. Using this cDNA as a probe, we demonstrated that expression of TM5/TM30nm mRNA was higher in the tumorigenic rat fibroblastic cell lines SR-3Y1-2 and fos-SR-3Y1-202 than in the normal cell line 3Y1. High expression of TM5/TM30nm protein in SR-3Y1-2 and fos-SR-3Y1-202 cells was also detected by Western blot analysis using anti-TM5/TM30nm antiserum. In addition, the cellular localization of this protein differed between 3Y1 cells and tumorigenic ones. These findings suggest that TM5/TM30nm is involved in malignant transformation of rat fibroblastic cells.

Amino Acid Sequence↗
PubMed1994

In vivo regulation of transforming growth factor beta 1 transcription by immunotherapy: interleukin-2 impairs interferon-alpha-stimulated increase in steady-state mRNA levels of transforming growth factor beta 1.

Recombinant interleukin-2 (rIL-2) in combination with recombinant interferon alpha (rIFN alpha) has been shown to mediate significant antitumoral effects in some patients with advanced renal cell cancer or malignant melanoma. The therapeutic effects may be partially modulated by secondarily induced cytokines, especially with regard to in vivo lymphocyte activation. To investigate possible negative effects on lymphocyte activation during immunotherapy, we designed a study on transcription of transforming growth factor beta 1 (TGF beta 1), a known inhibitor of lymphocyte function, in patients undergoing treatment with daily alternating administration of rIFN alpha and rIL-2. Here we present data on gene expression of TGF beta 1. Kinetic mRNA studies revealed an increase of TGF beta 1 mRNA in peripheral mononuclear cells 12 h after subcutaneous injection of rIFN alpha. The following intravenous rIL-2 administration significantly decreased the amounts of TGF beta 1-specific mRNA. In contrast to the effect of the first dose, subsequent application of rIFN alpha did not enhance TGF beta gene expression during rIFN alpha/IL-2 therapy. The diminished TGF beta 1 gene expression returned to pretreatment levels 1-7 days after the last rIL-2 administration. When concomitant with a decrease in TGF beta 1 transcripts. Our results indicate a complex regulatory effect on secondarily induced cytokines such as TGF beta 1 by immunotherapeutic approaches. The rIL-2-mediated down-regulation of increased TGF beta 1 steady-state mRNA levels following rIFN alpha may represent a positive immune regulatory effect on cytotoxic cells. Furthermore this effect may modulate proliferation of neoplastic tissues.

Autoradiography↗