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Scientific Background of Dermatopoietin®

Dermatopoietin® is our trade name for interleukin-1 alpha (IL-1 alpha), a cytokine of 159 amino acids. IL-1 alpha is best known to biologists as pyrogen and pro-inflammatory compound involved in the regulation of immune responses. But it is much more than that: as a pleiotropic factor it is expressed in many different tissues and exerts distinct and site-specific effects.

In normal human epidermis IL-1 alpha is produced on a constitutive basis by keratinocytes in substantial amounts. Growing evidence suggests that it plays an essential role in skin homeostasis and in the regulation of hair growth. 

History 

IL-1 alpha was discovered in 1981 as an epidermal cell-derived thymocyte-activating factor (NIH, USA). In 1986 it was detected in normal human epidermis (University Hospital, Geneva, Switzerland). Two years later IL-1 alpha was identified as a regulator of the turnover of extracellular matrix components of the dermis (University of California and University of Tennessee). In 1998 and 2002 it was found to be the primary inductor of epidermis renewal (Research institutions in Heidelberg and Zurich) and to be responsible for the maintenance of normal skin barrier function.

Role of IL-1 alpha in skin renewal 

In skin the functions of IL-1 alpha include the induction of epidermal growth through epithelial-mesenchymal interactions, the regulation of skin barrier function (lipid biosynthesis) and the regulation of the synthesis of extracellular matrix components ( collagen and elastin, among others) in the dermis.

In normal human epidermis 50% of IL-1 alpha present is found in the stratum corneum (outermost skin layer of dead cells) and 50% in living cells. Based on a specific activity of IL-1 alpha of 1x109 IU/mg the stratum corneum contains about 600 ng/g of IL-1 alpha, since an activity of about 6x105 IU per gram of stratum corneum was found by the specific LAF (lymphocyte-activating factor) test. All IL-1 activity in healthy human skin is IL-1 alpha activity. As reference, the normal blood level of IL-1 alpha is about 2 pg/ml. These figures imply that the skin is the major production site of IL-1 alpha but that skin also represents an isolated pool from the rest of the body. 

In contrast, the IL-1 beta isoform is the inducible form of IL-1 that is produced by mesenchymal cells upon stimulation. It has 26% identity with IL-1 alpha. Although the general opinion is that IL-1 alpha and beta effects are indistinguishable, there are data showing that this is not so.

IL-1 alpha seems to orchestrate the entire process of skin renewal by initiating a cascade of paracrine regulators, activating the proliferation of keratinocytes and fibroblasts, and regulating the synthesis/degradation of extracellular matrix components. In aging humans the content of IL-1 alpha in skin progressively diminishes which leads to impaired  skin renewal and the typical signs of skin aging. This offers the opportunity to compensate for this deficit by treating age-related symptoms with cosmetic preparations containing Dermatopoietin®. 

Mechanism of action 

Dermatopoietin® does not deliver any structural components to the skin. It rather acts by activating the tissue's own regenerative processes. Dermatopoietin®is too large polypeptide to penetrate the skin (see below). But this is not required as it acts in a non-penetrating manner: it only needs to make contact with the first layer of living cells in the epidermis to exert its activity. It stimulates these cells (keratinocytes) to produce and secrete IL-1 alpha themselves. By such an autocrine signaling mechanism the message of Dermatopoietin® propagates through the skin until the IL-1 alpha 'wave' reaches its main site of action, the fibroblasts in the dermis. IL-1 alpha activates these connective tissues cells to secrete and build up the extracellular matrix of the dermis, which consists of a network of collagen, elastin and other macromolecules. Fibroblasts in turn release a number of growth factors (keratinocyte growth factor (KGF), hepatocytes growth factor (HGF), granulocyte and macrophage colony stimulating factor (GM-CSF), and transforming growth factor-alpha (TGF-alpha)), which stimulate keratinocyte proliferation and differentiation in the basal layer of the epidermis in a paracrine manner. IL-1 alpha does not stimulate keratinocyte proliferation directly. In summary, topical application of Dermatopoietin® leads to a renewal of the skin structure across all its layers by autocrine and paracrine mechanisms.

Dermatopoietin does not penetrate the skin
 

The absorption and penetration of Dermatopoietin® was measured by exposing artificial human skin patches during 24 hours to high concentrations of fluorescence-labeled Dermatopoietin®(about 480'000 higher than the in-use concentration).

Fluorescence microscopy indicated that Dermatopoietin® was absorbed by the stratum corneum only without penetrating deeper layers. The detection limit of this method was estimated to be 20 pg/cm2.

Left figure: fluorescence microscopy. Green fluorescence indicates the presence of labeled Dermatopoietin®.

Right figure: light microscopic picture of the same field showing the artificial epidermis (EpiSkin) on a supporting polycarbonate membrane. Magnification: 100 x. Small circle: 10 m, large circle: 25 m

Quantitative relationships 
Normal stratum corneum contains about 0.6 g IL-1 alpha per gram of tissue. Assuming an average thickness of stratum corneum of 20 m and a density of 1 g/cm3 the relative amount of Dermatopoietin® applied with a cosmetic preparation compared to the endogenous IL-1 alpha is calculated as follows: Based on the 'SCCP's Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation' the standard application of a face cream is 0.8 g on an area of 565 cm2. The amount of stratum corneum of such a skin area is approximately 1.2 g which contains 0.7 g endogenous IL-1 alpha. The application of a cosmetic preparation with a concentration of Dermatopoietin® of 150 ng/g adds thus 120 ng of IL-1 alpha, which corresponds to some

17% of the IL-1 alpha present endogenously.

Role of IL-1 alpha in hair growth 

The effects of IL-1 alpha on hair follicle growth are complex. IL-1 alpha does not inhibit hair fiber growth but it seems to inhibit the proliferation of matrix keratinocytes. This effect is mediated by cAMP. However, at the same concentration IL-1 alpha also dramatically stimulates follicular papilla cells to express growth factors (KGF, HGF, GM-CSF, VEGF) required for keratinocyte proliferation, hair follicle development and differentiation, leading to hair growth and elongation as well as proper vasculature around the hair follicle during the anagen growth phase.

IL-1 alpha further stimulates the expression of PN1, the main marker of anagen hair follicles. PN1 is a serine protease inhibitor with activity against thrombin, plasminogen activators tPA and uPA, trypsin and plasmin. Thrombin is the main target of PN1. Thrombin receptors are present in hair follicles only during the catagen phase. Activated by thrombin they reduce the hair growth-supporting activity of follicle papilla cells (switch to catagen). PN1 co-localizes with thrombin and restricts its activity in follicles, which is associated with their switching to anagen. IL-1 alpha also suppresses androgen receptor expression by follicular papilla cells, a clear anti-androgenetic alopecia effect.

IL-1 alpha or IL-1 alpha-inducing agents reduced or prevented chemotherapy-induced alopecia and alopecia areata in human and in animal studies. These agents did not induce hair loss in these studies. The only case of IL-1 alpha-induced hair loss are transgenic mice constantly over-expressing IL-1 alpha in skin, a model far from reality.

These data suggest that the effects of IL-1 alpha are mediated by follicular papilla cells and that these effects are related to the anagen phase of hair follicles. Taking into consideration that IL-1 alpha is constitutively expressed in substantial amounts by keratinocytes and that this expression coexists with hair growth, these data strongly suggest a dominant role of IL-1 alpha in the regulation the normal human hair cycle.

Further reading ...