Interleukins 1α and 6 and Tumor Necrosis Factor-α Are Paracrine Inhibitors of Human Melanocyte Proliferation and Melanogenesis

Swope, Viki B.; Abdel‐Malek, Zalfa; Kassem, Lina M.; Nordlund, James J.

doi:10.1111/1523-1747.ep12460991

Cited by 238 publications

(178 citation statements)

References 21 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…In addition, in those MT-ret ϩ/Ϫ /IL-6 ϩ/Ϫ and MT-ret ϩ/Ϫ /IL-6 Ϫ/Ϫ mice that developed melanomas, the skin tumors were significantly smaller compared to MT-ret ϩ/Ϫ mice harboring two intact copies of the IL-6 gene. Previous in vitro studies have demonstrated that IL-6 can function as a growth inhibitory factor for early stage [13][14][15][16] and as a growth-promoting agent for later stage melanoma cells. 16,19,20 Our results show that, at least for the MTret ϩ/Ϫ mouse model of spontaneously developing melanomas, the tumor-promoting effect of IL-6 appears to be decisive, because reduction of IL-6 levels in MT-ret ϩ/Ϫ mice leads to a decrease both in melanoma incidence and in the size of primary melanoma nodules.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Felbert

Córdoba

Weissenberger

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Interleukin (IL)-6 is a pleiotropic cytokine that induces the acute phase response, stimulates B-and T-lymphocytes, and regulates the growth, differentiation, and death of several cell populations including neurons and melanocytes. 1-3 IL-6 promotes the development and progression of plasmacytomas 4 and gliomas 4,5 in vivo. It is also a growth-promoting factor for human basal cell carcinoma, Kaposi's sarcoma, and prostate cancer cells in vitro. 3,6 The IL-6 receptor system consists of IL-6 receptor ␣ (IL-6R␣), the primary IL-6 receptor, and the ubiquitous gp130 signal-transducing receptor subunit. Binding of IL-6 to its receptor complex leads to the activation of janus kinases (Jaks) and subsequent phosphorylation, dimerization, and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). 2,7 STAT3 promotes tumor progression by regulating the expression of genes involved in growth control such as c-myc, antiapoptosis [Bcl-x(L) and Mcl-1] and angiogenesis (vascular endothelial growth factor). 8 -11 In a recent study, STAT3 was found to be constitutively activated in some, but not all human melanoma cell lines and tumor specimens analyzed. 12 However, blocking experiments revealed that STAT3 activation in these cell lines was apparently mainly caused by Src tyrosine kinase activity and not by Jak activation. 12

show abstract

Section: Discussionmentioning

confidence: 99%

“…12 In vitro growth of early stage melanoma cells has been shown to be inhibited by IL-6 in several studies. [13][14][15][16] In the A375 cell line, this inhibition is mediated by IL-6-induced STAT activation. 17,18 Cells derived from advanced melanomas at metastatic stages often lose this anti-proliferative response to IL-6.…”

mentioning

confidence: 99%

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Felbert

Córdoba

Weissenberger

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Also certain breast and lung cancer cells respond with growth arrest to IL-6 and OSM (Chen et al, 1988;Douglas et al, 1997;Horn et al, 1990;Takizawa et al, 1993). Besides that, an anti-proliferative e ect of IL-6 and OSM has been described for melanocytes (Swope et al, 1991) and for melanoma cells from early phases of tumor growth (Lu et al, 1992(Lu et al, , 1993(Lu et al, , 1996Swope et al, 1991). In contrast, cells from advanced stage melanomas are in most cases resistant to IL-6 and/or OSM, acquiring the so-called`multicytokine resistance' phenotype.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Heinrich²,

et al. 1999

View full text Add to dashboard Cite

Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this e ect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 e ectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory e ect of OSM and IL-6 in A375 cells. In addition, we have identi®ed the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.

show abstract

“…Tumors, including melanoma, frequently develop resistance to growth inhibition by TGF-b, in part, through loss or deregulation of cdk inhibitors Fynan and Reiss, 1993). Another cytokine which can mediate G 1 arrest is interleukin-6 (IL-6) which is a potent growth inhibitor of normal melanocytes and of early stage melanoma cells, but not of cell lines isolated from advanced or metastatic melanoma (Jennings et al, 1991;Swope et al, 1991;Lu and Kerbel, 1993). IL-6 is a pleiotropc cytokine produced by a variety of cells, including endothelial cells, ®broblasts, keratinocytes, monocytes, macrophages, B and T cells, as well as by some cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…Other biological roles IL-6 is known to play include immunological and in¯ammatory reactions, cell di erentiation, angiogenesis and acute phase responses (Kishimoto et al, 1995;Kishimoto, 1989). Many of these activities involve autocrine or paracrine regulation of cell growth (Okamoto et al, 1997;Chiu et al, 1996;Eustace et al, 1993;Miki et al, 1989;Zhang et al, 1989;Kawano et al, 1988), motility (Swope et al, 1991) or apoptosis (Mizutani et al, 1995;Borsellino et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma

et al. 1999

View full text Add to dashboard Cite

Interleukins 1α and 6 and Tumor Necrosis Factor-α Are Paracrine Inhibitors of Human Melanocyte Proliferation and Melanogenesis

Cited by 238 publications

References 21 publications

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma

Contact Info

Product

Resources

About