Insulin‐like growth factor‐binding protein‐2 inhibits proliferation of human embryonic kidney fibroblasts and of IGF‐responsive colon carcinoma cell lines

Höflich, Andreas; Lahm, Harald; Blum, Werner; Kolb, Helmut J.; Wolf, Eckhard

doi:10.1016/s0014-5793(98)01011-4

Cited by 67 publications

(53 citation statements)

References 63 publications

(48 reference statements)

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“…A reduction in IGFBP-2 and IGFBP-4 in response to changes in local cytokine concentrations could alter the process of maturation of the enterocyte moving from the crypt to the apex of the villi, as changes in IGFBP-2 and IGFBP-4 would modify IGF-I and IGF-II bioavailability. Hoeflich et al (1998) have shown that in HT-29 cells and in other colonic cancer epithelial cell lines that exogenous IGFBP-2 inhibits cell proliferation. Thus, it can be speculated that both IL-1 and IL-6, by lowering further IGFBP-2 and IGFBP-4, could increase the proliferation rate.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Street

Miraki-Moud²,

Sanderson³

et al. 2003

Journal of Endocrinology

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Chronic inflammation is characterised by modifications in cytokine concentrations, whereas growth is mainly dependent on the GH-IGF axis. IGF-I bioavailability is modulated by a family of IGF-binding proteins (IGFBPs). The aim of the present study was to evaluate the interactions among interleukin-1 (IL-1 ), IL-6 and IGFBP secretion by intestinal cells to assess whether cytokines modulate IGFBP secretion, and in turn IGF-I and IGF-II bioavailability. The human colon carcinoma derived cell line Caco-2 was used as an in vitro model for its capacity to differentiate spontaneously. Experiments were carried out on day 4 (undifferentiated state) and day 14 (differentiated state) after plating. Carcinoembryonic antigen (CEA) was used as a marker of differentiation and increased in the conditioned media (CM) from days 4 to 14 (0·2 0·01 ng/ml per 10 5 cells vs 3·3 0·2 ng/ml per 10 5 cells, P,0·05). IGFBP-2 and IGFBP-4 secretion decreased concomitantly. Cells were stimulated with IL-1 and IL-6 at 1, 10 and 50 ng/ml, and with IL-1 and IL-6 in combination at the same dose of 1 and 10 ng/ml. IGF-I at 50 ng/ml was used as a control. Caco-2 cells expressed and secreted mainly IGFBP-2 and IGFBP-4 into the CM. On day 4, IL-1 (1 ng/ml) and IL-6 (10 and 50 ng/ml) reduced IGFBP-2 by 29 8%, and by 32 9 and 38 8% respectively (P,0·05). IGFBP-4 was also reduced by IL-1 at 1 and 50 ng/ml (-14 4% and -46 11% vs serum free medium (SFM) respectively, P,0·05), and IL-6 at 50 ng/ml (-46 15%, P,0·05). Both IGFBP-2 and IGFBP-4 were reduced by IL-1 and IL-6 in combination at 1 and 10 ng/ml (P,0·05). On day 14, IGFBP-2 band intensity was reduced at 10 ng/ml of IL-1 (-22 15% vs SFM, P,0·05) and at 50 ng/ml of both cytokines (-33% 8% and -13% 13% vs baseline respectively, P,0·05). IGFBP-4 band intensity decreased with 10 and 50 ng/ml of IL-1 (-35 11% and -46 15% vs SFM respectively) and IL-6 (-36% 10% and -46 15% vs SFM respectively). IL-1 and IL-6 in combination at 1 and 10 ng/ml reduced both IGFBP-2 and IGFBP-4.In conclusion, IGFBP-2 and IGFBP-4 secretion in CM decreased with Caco-2 cell differentiation. IGFBP-2 and IGFBP-4 were significantly decreased by IL-1 and IL-6 treatment in both the undifferentiated and differentiated state. Furthermore, these cytokines increased cell proliferation whereas total protein content was significantly reduced only at the higher concentrations of IL-6 and IL-1 . These findings suggest that interleukins modulate the IGF-IGFBP system in Caco-2 cells in vitro.

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Section: Discussionmentioning

confidence: 99%

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Street

Miraki-Moud²,

Sanderson³

et al. 2003

Journal of Endocrinology

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“…However, other studies have reported that renal levels of IGFBP-2 protein increase with the onset of glomerulosclerosis [43,49], and circulating IGFBP-2 levels may also be increased in diabetes [32,54,55]. In addition, a host of studies support IGFBP-2 having anabolic actions in different experimental cell models, although in other cell models it has also been reported to exert inhibitory effects [47,[56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line

Davis

Rodgers

Kelley

2008

Endocr

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In diabetic nephropathy, glomerular mesangial cells exhibit aberrant anabolic activity that includes excessive production of extracellular matrix (ECM) proteins, leading to crowding of filtration surface areas and possible renal failure. In the present study, a murine mesangial cell line (MES-13 cells) was studied to determine the roles of the renin-angiotensin system (RAS) and the insulin-like growth factor (IGF) axis in the anabolic response to elevated glucose levels. Culture of MES-13 cells in medium containing supra-physiological glucose concentrations (>5.5 mmol/l) resulted in increased production of ECM proteins including laminin, fibronectin, and heparan sulfate proteoglycan with concurrent increases in IGF-binding protein (IGFBP)-2 production. These responses were blocked by the angiotensin receptor antagonists saralasin and losartan, while exogenous angiotensin II (Ang II) treatment directly stimulated increases in ECM and IGFBP-2. In all experiments, IG-FBP-2 levels were correlated with anabolic activity implicating IGFBP-2 as a possible mediator in cellular responses to high glucose and Ang II. Such mediation appears to involve IGFBP-2 modulation of IGF-I signaling, since all responses to high glucose or Ang II were blocked by immuno-neutralization of IGF-I. These data suggest alterations in the IGF axis as key mechanisms underlying nephropathic responses of mesangial cells to Ang II and high glucose.

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“…Both in vitro studies and in vivo experiments in which IGFBP-2 has been overexpressed or genetically deleted suggest that IGFBP-2 may have dual roles in modulating IGF actions consistent with the model of IGFBP function. Overexpression of IGFBP-2 in cells in vitro has resulted in both increased and decreased growth (Hoflich et al, 1998, Hoeflich et al, 2000. When overexpressed in the circulation, IGFBP-2 inhibited growth in transgenic mice (Hoeflich et al, 1999(Hoeflich et al, , 2001.…”

Section: Discussionmentioning

confidence: 99%

IGF‐I and microglia/macrophage proliferation in the ischemic mouse brain

O'Donnell

Frederick

Krady

et al. 2002

Glia

132

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We have used a model of hypoxic-ischemic brain injury in adult male C57BL/6 mice to study insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP) expression in response to cerebral hypoxia-ischemia (H/I) in the adult mouse. A period of 20 min of H/I that resulted in histopathology in cortex, striatum, and thalamus was correlated with induction of mRNA for IGF-I, IGFBP-2, IGFBP-3, IGFBP-5, and glial fibrillary acidic protein (GFAP) by 4 days of recovery. Increased IGF-I mRNA was located within damaged regions and was surrounded by IGFBP-2 mRNA expression. The results of combined immunostaining/in situ hybridzation showed that the cells expressing IGFBP-2 mRNA were also GFAP-positive and comprised a subset of activated astrocytes immediately surrounding areas of damage. In contrast, staining within damaged regions showed high numbers of cells immunopositive for F4/80 and lectin B(4) indicative of microglia and macrophages but no cells immunopositive for the astrocytic proteins GFAP or S-100beta. Microglia/macrophages within the damaged areas expressed IGF-I mRNA and were also immunopositive for the proliferating cell nuclear antigen. To determine whether expression of IGF-I could contribute to proliferation of microglia, we treated purified cultures of adult brain microglia with IGF-I in the presence of (3)H-thymidine. IGF-I stimulated a twofold increase in DNA synthesis in cultures of adult brain microglia. Taken together with previous data demonstrating that IGF-I promotes proliferation of peripheral macrophages, these data support the hypothesis that IGF-I is an autocrine/paracrine mitogen for microglia/macrophages after H/I.

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Insulin‐like growth factor‐binding protein‐2 inhibits proliferation of human embryonic kidney fibroblasts and of IGF‐responsive colon carcinoma cell lines

Cited by 67 publications

References 63 publications

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells

Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line

IGF‐I and microglia/macrophage proliferation in the ischemic mouse brain

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