Induction of autocrine epidermal growth factor receptor ligands in human keratinocytes by insulin/insulin‐like growth factor‐1

Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory mechanism involved in epithelial homeostasis, and, possibly, hyperproliferative diseases. Insulin‐like growth factor (IGF)‐1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinocytes in situ. In this report, we demonstrate that IGF‐1/insulin induced production of keratinocyte‐derived autocrine growth factors that bind to the EGF receptor. Increased steady‐state mRNA levels for transforming growth factor alpha (TGF‐α) and for amphiregulin (AR) were observed upon incubation of keratinocytes with mitogenic concentrations of IGF‐1. IGF‐1 also induced production and secretion of TGF‐α and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF‐1 on cultured keratinocytes. These results suggest that stimulation of keratinocyte growth by IGF‐1 requires activation of an EGF receptor‐mediated autocrine loop. © 1995 Wiley‐Liss, Inc.

[1]  G. Plowman,et al.  Amphiregulin‐dependent proliferation of cultured human keratinocytes: Autocrine growth, the effects of exogenous recombinant cytokine, and apparent requirement for heparin‐like glycosaminoglycans , 1994, Journal of cellular physiology.

[2]  G. Plowman,et al.  Structure and function of human amphiregulin: a member of the epidermal growth factor family. , 1989, Science.

[3]  M. Herlyn,et al.  Monoclonal antibody 425 inhibits growth stimulation of carcinoma cells by exogenous EGF and tumor‐derived EGF/TGF‐α , 1990, Journal of cellular biochemistry.

[4]  D. Wilson,et al.  Insulin-like growth factors are mitogenic for human keratinocytes and a squamous cell carcinoma. , 1991, The Journal of investigative dermatology.

[5]  James T. Elder,et al.  Overexpression of transforming growth factor alpha in psoriatic epidermis. , 1989, Science.

[6]  C. Disteche,et al.  The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity , 1990, Molecular and cellular biology.

[7]  Harold L. Moses,et al.  Production and auto-induction of transforming growth factor-α in human keratinocytes , 1987, Nature.

[8]  R. Cancedda,et al.  In vitro paracrine regulation of human keratinocyte growth by fibroblast‐derived insulin‐like growth factors , 1992, Journal of cellular physiology.

[9]  D. P. Murphy,et al.  Synergistic effects of epidermal growth factor (EGF) and insulin-like growth factor I/somatomedin C (IGF-I) on keratinocyte proliferation may be mediated by IGF-I transmodulation of the EGF receptor. , 1991, The Journal of investigative dermatology.

[10]  U. Rodeck,et al.  Inhibition of TGFα-induced second messengers by anti-EGF receptor antibody-425 , 1990 .

[11]  James T. Elder,et al.  Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin. , 1992, The Journal of investigative dermatology.

[12]  A. Gottlieb,et al.  The insulin-like growth factor I receptor is overexpressed in psoriatic epidermis, but is differentially regulated from the epidermal growth factor receptor , 1992, The Journal of experimental medicine.

[13]  V. Morhenn,et al.  Characterization of insulin-like growth factor-I/somatomedin-C receptors on human keratinocyte monolayers. , 1986, The Journal of investigative dermatology.

[14]  T. Horn,et al.  TGF-α Is Widely Expressed in Differentiated as well as Hyperproliferative Skin Epithelium , 1991 .

[15]  P. Jensen,et al.  A high-affinity receptor for urokinase plasminogen activator on human keratinocytes: characterization and potential modulation during migration. , 1990, Cell regulation.

[16]  L. Dubertret,et al.  Psoriatic fibroblasts induce hyperproliferation of normal keratinocytes in a skin equivalent model in vitro. , 1985, Science.

[17]  M. Herlyn,et al.  Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects. , 1987, Cancer research.

[18]  G. Laurent,et al.  * Author for correspondence Summary , 2022 .

[19]  M. Pittelkow,et al.  Growth factor‐independent proliferation of normal human neonatal keratinocytes: Production of autocrine‐ and paracrine‐acting mitogenic factors , 1991, Journal of cellular physiology.

[20]  H. Green,et al.  Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes , 1977, Nature.

[21]  R. Coffey,et al.  Amphiregulin messenger RNA is elevated in psoriatic epidermis and gastrointestinal carcinomas. , 1992, Cancer research.

[22]  U. Rodeck,et al.  Cytokine-induced expression of transforming growth factor-alpha and the epidermal growth factor receptor in neonatal skin explants. , 1992, The Journal of investigative dermatology.

[23]  B. Nickoloff,et al.  The cytokine network in psoriasis. , 1991, Archives of dermatology.

[24]  L. Nanney,et al.  Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. , 1984, The Journal of investigative dermatology.

[25]  M. Herlyn,et al.  Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide. , 1987, Archives of biochemistry and biophysics.

[26]  A. Allison,et al.  Autocrine stimulation of interleukin-1α and transforming growth factorα production in human keratinocytes and its antagonism by glucocorticoids , 1991 .

[27]  R. Akhurst,et al.  Localization of elevated transforming growth factor-alpha in psoriatic epidermis. , 1990, The Journal of investigative dermatology.

[28]  J. Adelman,et al.  A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin , 1991, Molecular and cellular biology.

[29]  M. Herlyn,et al.  Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. , 1991, The Journal of investigative dermatology.

[30]  E. Chen,et al.  Human transforming growth factor-α: Precursor structure and expression in E. coli , 1984, Cell.

[31]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[32]  C. Croce,et al.  Molecular cloning and nucleotide sequence of a full-length cDNA for human alpha enolase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Gottlieb,et al.  Detection of transforming growth factor alpha in normal, malignant, and hyperproliferative human keratinocytes , 1988, The Journal of experimental medicine.

[34]  L. Nanney,et al.  Altered [125I]epidermal growth factor binding and receptor distribution in psoriasis. , 1986, The Journal of investigative dermatology.