Epidermal growth factor-related peptides and their receptors in human malignancies

Protein tyrosine kinases (PTKs) regulate cell proliferation, cell differentiation, and signaling processes in the cells of the immune system. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases can lead to inflammatory responses and to diseases such as cancer, atherosclerosis, and psoriasis. Thus, inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate may provide a useful basis for drug development. This article summarizes recent progress in the development of PTK inhibitors and demonstrates their potential use in the treatment of disease.

https://science.sciencemag.org/content/sci/267/5205/1782.full.pdf

Tyrosine kinase inhibition: an approach to drug development

Tyrosine Kinase Inhibition: AnApproach toDrug Development

https://www.jidonline.org/article/S0022-202X(15)33382-0/pdf

Keratinocyte–Fibroblast Interactions in Wound Healing

Psoriasis is a common papulosquamous skin disease. The histopathology is characterized by epidermal hyperplasia and inflammation. Recent studies suggest that keratinocyte proliferation and inflammation in psoriasis are manifestations of the same underlying pathological process. Interleukin 6 (IL-6), a cytokine that is a major mediator of the host response to tissue injury and infection, is produced by both keratinocytes and leukocytes in culture. IL-6 expression was studied in psoriatic plaques by immunoperoxidase staining with two different polyclonal anti-recombinant IL-6 antisera and by in situ nucleic acid hybridization with IL-6 cRNA probes. Epidermal and dermal cells in active psoriatic plaques from 35 psoriasis patients stained heavily for IL-6 as compared with nonlesional skin and with plaques after treatment with antimetabolic and antiinflammatory agents. Absorption of the anti-recombinant IL-6 antisera with purified fibroblast-derived IL-6 or with recombinant IL-6, but not bovine serum albumin, removed the immunostaining. Increased levels of IL-6 were detected in the plasma of patients with active psoriasis (mean 3 ng/ml) by using two different bioassays. IL-6 production by proliferating keratinocytes was suggested by IL-6-specific immunostaining in cultured normal and psoriatic keratinocytes and by the detection of mRNA specific for IL-6 in psoriatic epidermis by in situ hybridization. IL-6 stimulated the proliferation of cultured, normal human keratinocytes as assessed by two different assays. Thus, IL-6 could directly contribute to the epidermal hyperplasia seen in psoriatic epithelium as well as affect the function of dermal inflammatory cells.

Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.

Transforming growth factor alpha (TGF-alpha) is produced by and required for the growth of epithelial cells and is angiogenic in vivo. Since epidermal hyperplasia and angiogenesis are hallmarks of psoriasis, TGF-alpha gene expression was analyzed in epidermal biopsies of normal and psoriatic skin. TGF-alpha messenger RNA and protein are much more abundant in lesional psoriatic epidermis than in normal-appearing skin of psoriatic patients or in normal epidermis. In contrast, messenger RNA levels of transforming growth factor beta 1 (TGF-beta 1), which inhibits epithelial cell growth, are not significantly different in normal, uninvolved, and lesional psoriatic epidermis. Thus, psoriatic epidermal hyperplasia may involve increased expression of a keratinocyte mitogen (TGF-alpha) rather than deficient expression of a growth inhibitor (TGF-beta 1).

https://science.sciencemag.org/content/sci/243/4892/811.full.pdf

Overexpression of transforming growth factor α in psoriatic epidermis

Differential modulation of transforming growth factor-β1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin

Psoriasis is a common skin disease, affecting 1 to 2 % of the U.S. population at a cost of some 1.5 billion dollars per year.’ Psoriasis is characterized by marked increases in keratinocyte proliferation? abnormal patterns of keratinocyte differentiation? prominent alterations in dermal capillary vasculature~ and the presence of dermal and epidermal T cells, monocytehacrophages, and polymorphonuclear leukocytes?.6 We have recently shown that expression of transforming growth factor-a (TGF-a) is markedly increased in psoriatic lesions: This result, coupled with the fluctuating clinical course of psoriasis, suggests that the molecular pathogenesis of psoriasis may involve unstable or altered regulation of TGF-a and possibly other epidermally derived cytokines, such as interleukin-6 (IL-6).8 Transforming growth factor-p (TCF-P) acts synergistically with TCF-a to promote anchorage-independent growth of certain cell types? However, it has potent antiproliferative effects upon a variety of epithelial cell types in vitro,’O including keratinocytes.“ In human keratinocytes, TGF-P causes a reversible inhibition of proliferation, predominantly in the GI phase of the cell cycle.I2 On the basis of these results, it has been hypothesized that TGF-p functions as a negative growth regulator in normal skin.ll,12 Given the marked keratinocyte hyperproliferation characteristic of psoriasis, it is possible that psoriatic keratinocytes could be deficient in either the production of or responsiveness to TGF-p, resulting in a deficient state of growth regulation. We have tested this hypothesis in several different ways with respect to TGF-P1, the first member of the TGF-0 gene family to be molecularly cloned and biochemically characterized. First, we have compared the expression of TGF-01 mRNA in normal and psoriatic epidermis by Northern blotting. These results confirm those already reported using a slot blot procedure? Second, we have compared the responsiveness of keratinocytes cultured from the skin of normal individuals and from psoriatic lesions to purified TCF-pl. The responses studied include TGF-p1-induced alterations in c-myc and plasminogen activator inhibitor-1 (PAI-1) mRNA levels as well as the proliferative response.

Larry Ellingsworth

Papers

Overexpression of transforming growth factor α in psoriatic epidermis

Differential modulation of transforming growth factor-β1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin

Transforming growth factor-β in psoriasis. Pathogenesis and therapy