Effects of insulin-like growth factors and growth hormone on the in vitro proliferation of T lymphocytes (original) (raw)
Related papers
Early effects of insulin-like growth factor-1 in activated human T lymphocytes
Journal of …, 2001
This study evaluates the effects of insulin-like growth factor (IGF)-1 receptor (IGF-1R) down-regulation in stimulated T lymphocytes by investigating the expression of early activation proteins CD69, CD25, and interleukin (IL)-2. We found that IGF-1 does not modify CD69 expression but increases transcription and protein synthesis of CD25 and IL-2. The lowest level of IGF-1R detected after 15 min of activation suggested that the effects of IGF-1 occur at the initiation of cell activation. The activation of IGF-1R was confirmed by IGF-1R phosphorylation and increased phosphorylation of microtubule-associated protein kinase. We also detected the alternative IGF-1 transcripts Ea, with paracrine/autocrine regulation, and Eb, with endocrine regulation, in Jurkat cells and in quiescent T lymphocytes, and we detected IGF-1 protein in the culture medium after stimulation. These data suggest that the proliferative effects of IGF-1 on T lymphocytes include both autocrine/paracrine and endocrine processes. J. Leukoc. Biol. 70: 297-305; 2001.
Human Immunology, 2005
Increasing evidence has implicated that insulin-like growth factors (IGFs), polypeptides structurally related to proinsulin, are involved in the function and development of the immune system. To probe the relevance of IGF binding protein 2 (IGFBP-2) in T-cell activation and proliferation, we studied the role of IGFBP-2 in anti-CD3 monoclonal antibody (mAb)-activated peripheral blood mononuclear cells (PBMCs). Secretion of IGF-I, IGF-II, and IGFBP-2 by PBMCs from healthy adult donors was determined by radioimmunoassays (RIAs). The PBMC proliferative response after stimulation with anti-CD3 mAb and exposure to increasing concentrations of IGF-I, IGF-II, IGFBP-2, and anti-IGFBP-2 were determined by bromodeoxyuridine enzyme-linked immunosorbent assay. Observations were tested for significance by paired t-tests. We demonstrate an increase in IGFBP-2 secretion associated with both activation of PBMC by anti-CD3 mAb and increasing cell density. Incubation with exogenous IG-FBP-2 increased the proliferation of PBMCs, whereas anti-IGFBP-2 had an antiproliferative effect on PBMCs that was reversed by simultaneous exposure to IGFBP-2. The stimulatory activity of IGFBP-2 (1-10 ng/ml) on anti-CD3 mAb-activated PBMCs was similar to that of IGF-I and IGF-II (1-100 ng/ml), with the mean increase in PBMC proliferative response ranging between 150% and 160% for IGFBP-2 (p ϭ 0.03), 150% and 170% for IGF-I (p Ͻ 0.01), 133%-161% for IGF-II (p Ͻ 0.01), and 157% and 175% for IGF-I ϩ IGF-II (p Ͻ 0.01). Thus, our data strongly suggest a role for IGFBP-2 as a local growth factor contributing to the proliferation and activation of mononuclear cells.
Hum Immunol, 2005
Increasing evidence has implicated that insulin-like growth factors (IGFs), polypeptides structurally related to proinsulin, are involved in the function and development of the immune system. To probe the relevance of IGF binding protein 2 (IGFBP-2) in T-cell activation and proliferation, we studied the role of IGFBP-2 in anti-CD3 monoclonal antibody (mAb)-activated peripheral blood mononuclear cells (PBMCs). Secretion of IGF-I, IGF-II, and IGFBP-2 by PBMCs from healthy adult donors was determined by radioimmunoassays (RIAs). The PBMC proliferative response after stimulation with anti-CD3 mAb and exposure to increasing concentrations of IGF-I, IGF-II, IGFBP-2, and anti-IGFBP-2 were determined by bromodeoxyuridine enzyme-linked immunosorbent assay. Observations were tested for significance by paired t-tests. We demonstrate an increase in IGFBP-2 secretion associated with both activation of PBMC by anti-CD3 mAb and increasing cell density. Incubation with exogenous IG-FBP-2 increased the proliferation of PBMCs, whereas anti-IGFBP-2 had an antiproliferative effect on PBMCs that was reversed by simultaneous exposure to IGFBP-2. The stimulatory activity of IGFBP-2 (1-10 ng/ml) on anti-CD3 mAb-activated PBMCs was similar to that of IGF-I and IGF-II (1-100 ng/ml), with the mean increase in PBMC proliferative response ranging between 150% and 160% for IGFBP-2 (p ϭ 0.03), 150% and 170% for IGF-I (p Ͻ 0.01), 133%-161% for IGF-II (p Ͻ 0.01), and 157% and 175% for IGF-I ϩ IGF-II (p Ͻ 0.01). Thus, our data strongly suggest a role for IGFBP-2 as a local growth factor contributing to the proliferation and activation of mononuclear cells.
Immunology and Cell Biology, 1994
In a serum-free medium addition of insulin-like growth factor-1 (IGF-1) consistently enhanced lymphocyte proliferation response to PHA in a dose-dependent fashion. This effect was produced by an acceleration in the expression of clone expansion and not in the number of proliferating cells. This was documented by kinetics data obtained from the first proliferation round of PHAstimulated lymphocytes, in which addition of IGE-1 reduced Gj-phase length, without changing Gophase, S-phase or cloned size. The data were confirmed in 10-day culture of stimulated lymphocytes where IGF-1 only accelerated cell proliferation without modifying the area enclosed by the proliferation curve. As IGF-1 is under the control of growth hormone, our results suggest that some ofthe immunoregulation effects ascribed to grovrth hormone in vivo could be produced by IGF-I.
Immunology, 1998
The expression of the insulin-like growth factor binding protein-2 (IGFBP-2) was assayed in mononuclear cells originating from different organs of the immune system. All mononuclear cells studied did express IGFBP-2, but the expression level was found to be dependent on the cell type and origin of the cell. T cells showed a higher expression of IGFBP-2 mRNA than did B cells, and CD34+ stem cells expressed IGFBP-2 mRNA at a high level. Expression was highest in bone marrow and thymus. Stimulation of peripheral mononuclear cells resulted in a marked increase of IGFBP-2 mRNA and also intracellular IGFBP-2, as analysed by fluorescence staining. This increase parallels the increase of other known T-cell activation markers. Furthermore, the increase of intracellular IGFBP-2 seems to precede T-cell blast formation and all T cells in active phases of the cell cycle have high levels of IGFBP-2. Our results provide a basis for further investigations on the contribution of the IGF-system to the regulation of T-cell proliferation and differentiation. IGFBP-2, in particular, may have an important influence in the regulation of T-cell activation and proliferation.
The expression of insulin-like growth factors and their binding proteins in normal human lymphocytes
European Journal of Endocrinology, 1993
... Cell 57: 1053-1063, 1989 5. Beck F, Samani NJ, Penschow JD, Thorley B, Tregear GW, Coghlan JP: Histochemical localization of IGF-I and -II mRNA in the developing rat embryo. Development 101: 175-184,1987 6. Stylianopoulou F, Efstradiadis A, Herbert J, Pintar J: Pat-tern ...
Leukemia, 1998
The role of insulin (INS), and insulin-like growth factor-I (IGF-I) in the regulation of human erythropoiesis is not completely understood. To address this issue we employed several complementary strategies including: serum free cloning of CD34 ؉ cells, RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). In a serum-free culture model, both INS and IGF-I enhanced survival of CD34 ؉ cells, but neither of these growth factors stimulated their proliferation. The influence of INS and IGF-I on erythroid colony development was dependent on a combination of growth factors used for stimulating BFU-E growth. When BFU-E growth was optimally stimulated with erythropoietin (EpO) ؉ kit ligand (KL) the large erythroid colonies developed normally even in the absence of INS or IGF-I. However, the addition of both of these growth factors slightly enhanced colony size. On the other hand, if eruthroid colonies were stimulated suboptimally with EpO + IL-3 only, INS or IGF-I increased the number of small erythroid bursts by ෂ30%. Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34 ؉ , c-kit-R ؉ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34 ؉ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34 ؉ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.
Regulation of Myeloid Growth and Differentiation by the Insulin-Like Growth Factor I Receptor1
Endocrinology, 1997
Flow cytometry was used to examine the expression of type I insulin-like growth factor receptors (IGF-IR) on three types of human hematopoietic cells that represent different stages of myeloid lineage development. Both HL-60 (promyeloid) and U-937 (monocytic) cells express abundant IGF-IR protein (Ͼ79% cells positive for the IGF-IR), whereas KG-1 myeloblasts express negligible levels of IGF-IR (Ͻ1% IGF-IR-positive cells). Exogenous IGF-I, IGF-II, and an IGF-I analog that binds poorly to IGF-binding protein-3 (des-IGF-I) increased DNA synthesis of HL-60 and U-937 cells in a dose-dependent (1-25 ng/ml) fashion by 2-to 4-fold in serum-free medium, whereas KG-1 cells did not respond to any of these growth factors. The IGFinduced increase in proliferation of HL-60 promyeloid cells was inhibited by soluble IGF-binding protein-3 (500 ng/ml) when these cells were stimulated with 10 ng/ml of either IGF-I (53 Ϯ 8%) or IGF-II (59 Ϯ 8%), but not with des-IGF-I (3 Ϯ 1%). In contrast, the anti-IGF-IR monoclonal antibody (mAb; ␣IR-3) inhibited the DNA synthesis caused by 10 ng/ml exogenous IGF-I (67 Ϯ 6%), IGF-II (72 Ϯ
Endocrinology, 2000
The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal human thymus. By reverse transcriptase polymerase chain reaction (RT-PCR) analyses, promoters P3 and P4 were found to be active in the transcription of IGF2 gene within human thymic epithelial cells (TEC). No IGF-II mRNA could be detected in human lymphoid Jurkat T cells with 30 cycles of RT-PCR. By Northern blot analyses, IGFBP-2 to -6 (but not IGFBP-1) were found to be expressed in TEC with a predominance of IGFBP-4. Interestingly, Jurkat T cells only express IGFBP-2 but at high levels. The type 1 IGF receptor was detected in Jurkat T cells but not in human TEC. The identification of the components of the IGF axis within separate compartments of the human thymus adds further evidence for a role of this axis in the control of T-cell development. The precise influence of thymic IGF axis upon T-cell differentiation and immunological self-tolerance however needs to be further investigated.