Growth inhibition of human colorectal‐carcinoma cells by interleukin‐4 and expression of functional interleukin‐4 receptors

Lahm, Harald; Schnyder, Bruno; Wyniger, Josiane; Borbényi, Zita; Yilmaz, Aysim; Car, Bruce D.; Fischer, Jürgen R.; Givel, Jean-Claude; Ryffel, Bernhard

doi:10.1002/ijc.2910590325

Cited by 26 publications

(19 citation statements)

References 34 publications

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“…In normal breast tissues, gp200-MR6 is expressed on both luminal epithelium and myoepithelium (moderate in 86% of cases, strong in 7% of cases). In benign hyperplastic tissues, the expression of gp200-MR6 was heterogeneously distributed, with moderate staining (+ +) in some cells and no staining (-) (Tepper et al, 1989) and an antitumour effect in vivo in the nude mouse xenograft model (Lahm et al, 1994). The role, if any, of gp200-MR6 in such tumour suppression is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast

Al-Tubuly

Luqmani²,

Shousha³

et al. 1996

Br J Cancer

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Summary In this study, we used immunohistochemical and biochemical analysis to show that gp200-MR6, a 200 kDa molecule that is functionally associated with the human interleukin 4 (IL-4) receptor complex, is expressed at high levels on normal breast epithelial tissues, at lower levels on in situ carcinomas, and that the expression is lost in the invasive carcinoma of the breast. Furthermore, a preliminary study showed that benign epithelial hyperplasia of the breast expresses the gp200-MR6 heterogeneously. Two populations of cells have been observed: MR6 positive and MR6 negative. Interestingly, MR6-positive cells were observed to have different morphology from those that were MR6 negative; the nuclei of the former were larger and rounded in shape, whereas the nuclei of the latter were relatively small and oval in shape. In sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting, monoclonal antibody MR6 detects the same molecular weight molecule in both normal and transformed tissue, indicating that the molecule is not a product of a truncated gene. The intensity of the gp200-MR6 bands correlates with the immunohistochemical data, indicating that the molecule is expressed at high levels in normal tissue and at lower levels in malignant tissue. These results suggest that analysis of gp200-MR6 expression may be useful in tumour grading and prognostic evaluation in breast cancer. Moreover, the molecule may be involved early in the process of tumorigenesis of the breast, in which a loss or a down-regulation of gp200-MR6 could contribute towards tumour development and progression via an effect on cell growth and differentiation.

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Section: Discussionmentioning

confidence: 99%

Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast

Al-Tubuly

Luqmani²,

Shousha³

et al. 1996

Br J Cancer

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“…In cancer cells, IL-4 often promotes proliferation, metastasis, and expression of anti-apoptotic genes (13)(14)(15)(16). On the other hand, we and others have shown that IL-4 directly inhibits growth of several human cancer cell lines including those derived from breast, gastric, colon, and renal cancers (17)(18)(19)(20)(21)(22). In addition, apoptosis can be induced or suppressed by IL-4: IL-4 induced apoptosis in certain cell types, including breast and liver cancer cells, hepatocytes, endothelial cells, monocytes, and developing mast cells (23)(24)(25)(26), whereas it increased resistance to apoptosis in mouse fibrosarcoma cell lines and STAT6-high human cancer cell lines such as HT-29 and ZR-75-1 (16,27).…”

Section: Interleukin (Il)mentioning

confidence: 98%

“…inhibits cell growth in several human cancer cell lines with or without inducing apoptosis (17)(18)(19)(20)(21)(22)28). To evaluate the effects of IL-4 on the growth of human RCC cells, Caki-1, A498, and 786-O cells were exposed to 1-10 ng/ml of IL-4 for 24 h, and cell proliferation was measured by a […”

Section: Il-4 Inhibits Growth Of Human Rcc Cells-il-4mentioning

confidence: 99%

Interleukin-4 Induces Senescence in Human Renal Carcinoma Cell Lines through STAT6 and p38 MAPK

Kim

et al. 2013

Journal of Biological Chemistry

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Background: IL-4 can directly inhibit growth of several tumor cell types, but the molecular mechanism is not known. Results: IL-4 induces senescence by increasing p21 WAF1/CIP1 expression through STAT6 and p38 MAPK. Conclusion: STAT6 and p38 MAPK play important roles in senescence induction by IL-4. Significance: This is the first report of cellular senescence induction by IL-4 and the responsible mechanism.

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“…Other workers have reported that IL-4 inhibited the growth of breast (MCF-7) and colorectal (HT29, WiDr, LS411N, LS513 and LS1034) carcinoma cell lines in culture by 45-75% at 100 U/ml, while competitive binding of 125 I-IL-4 demonstrated the presence of 2,000 high-affinity IL-4 binding sites/cell on the HT29 cell line (Toi et al, 1992;Lahm et al, 1994). It has also been shown that human renal cell carcinoma expresses high-affinity IL-4R and that IL-4 inhibits tumour growth in vitro (Obiri et al, 1993).…”

Section: Both Mab Mr6 and Il-4 Induce Glandular Differentiation Of Swmentioning

confidence: 99%

“…For B cells, T cells, capillary endothelium and mast cells, IL-4 acts as a growth factor (Toi et al, 1991;Defrance et al, 1987;Mosmann et al, 1986;Howard et al, 1982). In contrast, IL-4 has been shown to have a growth inhibitory effect on human colon, renal and breast carcinoma cell lines, (Toi et al, 1992;Obiri et al, 1993;Lahm et al, 1994). Using immunohistochemical and biochemical analysis (Al-Tubuly et al, 1996) for a range of breast tissues, we have demonstrated that gp200-MR6 is weakly expressed on carcinoma in situ and lost on invasive tumours of the breast, while it is strongly expressed on the normal counterparts of the same tissue.…”

mentioning

confidence: 99%

Inhibition of growth and enhancement of differentiation of colorectal carcinoma cell lines by MAb MR6 and IL-4

et al. 1997

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We have previously shown that expression of gp200-MR6, a molecule that is functionally associated with the interleukin-4 receptor (IL-4R), is lost from breast carcinoma cells as malignancy increases. Here we have analysed a series of colorectal carcinoma cell lines and show a similar decrease with increasing malignancy. Moreover, analysis of the HRA-19 cell line, which can exhibit a poorly or a well-differentiated phenotype according to culture conditions, shows that gp200-MR6 is weakly expressed on the former but strongly expressed on the latter. Functional analysis using either IL-4 or monoclonal antibody (MAb) MR6 and the well-differentiated cell line SW1222 revealed that MAb MR6 acts as an agonist for IL-4, with both reagents causing a dose-dependent inhibition of cell division, but greatly enhancing the glandular differentiation of SW1222 in three-dimensional collagen gels. These observations suggest that the gp200-MR6 molecule may act as the product of a tumour suppressor gene and that its loss may be a primary event in tumourigenesis. Int. J. Cancer 71: 605-611, 1997.r 1997 Wiley-Liss, Inc.MAb MR6 is a murine IgG 1 antibody, raised against human thymic stromal cells as part of a study designed to investigate the role of the human thymic microenvironment in T-cell maturation (De Maagd et al., 1985). It stains strongly the cortical epithelium and relatively weakly the macrophages and dendritic cells in frozen tissue sections of human thymus (Larché et al., 1987). Immunoelectron microscopy showed that this labelling was localised mainly on the surface of these cells (von Gaudecker et al., 1996). A single band of approximately 200 kDa (gp200-MR6) was detected from biochemical analysis by immuno-precipitation and Western blotting using lysates from normal thymus (Mat et al., 1990). This m.w. was the same under reducing and non-reducing conditions.In functional studies, it was found that MAb MR6 can completely block the proliferation of helper T cells induced by recombinant interleukin-4 (rIL-4) and can block the IL-4-induced production of IgE by polyclonal B cells in the presence of cloned T cells (Larché et al., 1988). Since MAb MR6 also inhibits the production of IL-4 by antigen-activated T cells, it is likely that the major target in these experiments is the IL-4-producing T-helper (Th2) lymphocyte subset (Imami et al., 1994). These data, together with the molecular characteristics of gp200-MR6 and the finding that MAb MR6 does not block the binding of IL-4 to its receptor (IL-4R), have led to the suggestion that MAb MR6 may recognise a polypeptide chain associated with the 140 kDa IL-4R (CD 124) that is possibly involved in IL-4 signal transduction (Larché et al., 1988). Human IL-4, a 19 kDa cytokine, is produced primarily by CD4 1 and some CD8 1 T cells (Paliard et al., 1988); however, it has also been suggested that IL-4 might be produced by bone marrow stromal cells (King et al., 1988), mast cells (Mitchell et al., 1989) and basophils (Brunner et al., 1993). For B cells, T cells, capillary endothelium a...

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Growth inhibition of human colorectal‐carcinoma cells by interleukin‐4 and expression of functional interleukin‐4 receptors

Cited by 26 publications

References 34 publications

Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast

Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast

Interleukin-4 Induces Senescence in Human Renal Carcinoma Cell Lines through STAT6 and p38 MAPK

Inhibition of growth and enhancement of differentiation of colorectal carcinoma cell lines by MAb MR6 and IL-4

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