Oak, Green Tea and Orange Derivatives to Disrupt JAK/STAT, NF-κB Irritation Pathways

Jan 1, 2011 | Contact Author | By: Giorgio Dell’Acqua, PhD; Kuno Schweikert, PhD; and Giuseppe Calloni, Induchem AG
Your message has been sent.
(click to close)
Contact the Author
Save
This item has been saved to your library.
View My Library
(click to close)
Save to My Library
Title: Oak, Green Tea and Orange Derivatives to Disrupt JAK/STAT, NF-κB Irritation Pathways
soothingx irritationx NF-κBx JAK/STATx keratinocytex
  • Article
  • Media
  • Keywords/Abstract

Keywords: soothing | irritation | NF-κB | JAK/STAT | keratinocyte

Abstract: Activation of NF-κB and JAK/STAT pathways in keratinocytes leads to the release of immunomodulating factors that sustain an amplification loop between the keratinocyte and infiltrating immune cell, leading to skin irritation. To disrupt this loop, two complexes, one based on oak and green tea extracts, and another on orange flavonoids, were developed and are shown here to immediately soothe skin.

View citation for this article

G Dell'Acqua, K Schweikert and G Calloni, Oak, Green Tea and Orange Derivatives to Disrupt JAK/STAT, NF-κB Irritation Pathways, Cosmet & Toil 126(1) 30 (2011)

Excerpt Only This is a shortened version or summary of the article you requested. To view the complete article, please log in or create an account. Registration is Free!

Skin is exposed to the external environment that brings with it daily aggressions such as UV light, chemicals, pollution, temperature, etc. These aggressions can create skin irritation, especially in sensitive skin individuals, leading to itching and discomfort. Moreover, in the long-term, irritation leads to skin damage and premature aging as a result of elastosis and matrix degradation.1-3 It is therefore important to stop skin irritation rapidly to not only reduce skin discomfort, but also avoid further skin damage.

Skin irritation is sustained by a cross-talk mechanism between a keratinocyte in the epidermis layer and the infiltrating immune cell, e.g. T lymphocytes. This cross-talk creates an amplification loop that leads to overreaction and escalates the inflammatory process with consequent skin erythema and irritation. Under these circumstances, the skin is unbalanced and requires re-balancing.

NF-κB and JAK/STAT Pathways

The NF-κB and JAK/STAT signaling pathways are both dramatically amplified in dermatological conditions and play substantial roles in sustaining skin irritation.4 In the NF-κB pathway, a cytokine receptor expressed on the cell membrane of the keratinocyte will recognize cytokine ligands produced by skin-infiltrating immune cells, thus triggering the release in the cytoplasm of the NF-κB unit, which is normally sequestered by a family of inhibitory proteins known as inhibitors of NF-κB (IκBs). The signaling pathway from the receptor will lead to the liberation and nuclear accumulation of NF-κB, in turn activating the transcription of pro-inflammatory molecules such as cytokines and chemokines.5, 6

Excerpt Only This is a shortened version or summary of the article you requested. To view the complete article, please log in or create an account. Registration is Free!

Media

Figures

 

Close

Table 1. Treatment of human keratinocytes with the PN complex at 0.4% inhibits cytokine mix-induced pro-inflammatory mRNA profile; data is expressed in % vs untreated control

Table 1. Treatment of human keratinocytes with the PN complex at 0.4% inhibits cytokine mix-induced pro-inflammatory mRNA profile; data is expressed in % vs untreated control

NHEK incubated with the PN complex were extracted for mRNA after 24 hr, the mRNA was reverse-transcribed, and genes for JAK/STAT signalling as well as chemokines and cytokines were analyzed (see Table 1).

Table 2. Placebo products used for in vivo studies to test the PN complex in a cream, and the EG complex in a gel

Table 2. Placebo products used for in vivo studies to test the PN complex in a cream, and the EG complex in a gel

After skin irritation was induced, test formulas (see Table 2) were applied blindly following their usual use to volunteers. In the first group of volunteers, four of the irritated areas were treated with a water-based gel containing the EG complex at varying concentrations; in the second group of volunteers, four irritated areas were treated with a cream containing the PN complex at different concentrations.

Figure 1. The tested complexes were designed to inhibit the NF-κB and JAK/STAT activated signaling pathways in keratinocytes to interrupt communication between the keratinocyte and immune cell, providing an immediate soothing effect.

Figure 1. The tested complexes were designed to inhibit the NF-κB and JAK/STAT activated signaling pathways in keratinocytes to interrupt communication between the keratinocyte and immune cell, providing an immediate soothing effect.

The hypothesis was then to test, in human keratinocytes, the ability of the EG and PN complexes to inhibit the NF-κB and JAK/STAT signaling pathways and subsequent cytokine and chemokine expression and release leading to pro-inflammatory cross-talk and skin irritation (see Figure 1).

Figure 2. Treatment with 0.4% PN complex inhibited JAK/STAT signaling proteins in human keratinocytes induced with a cytokines mixture; * = statistically significant.

Figure 2. Treatment with 0.4% PN complex inhibited JAK/STAT signaling proteins in human keratinocytes induced with a cytokines mixture; * = statistically significant.

As shown in Table 1 and Figures 2, 3 and 4, treatment of NHEK with the Oncostatin M + IL-17 + TNF-a cytokine mix dramatically increased the transcription of JAK/ STAT signaling markers, cytokines and chemokines mRNA; by 681%, 3,744% and 10,761%, respectively.

Figure 3. Treatment with 0.4% PN complex inhibited cytokine synthesis in human keratinocytes induced with a cytokine mixture; * = statistically significant.

Figure 3. Treatment with 0.4% PN complex inhibited cytokine synthesis in human keratinocytes induced with a cytokine mixture; * = statistically significant.

As shown in Table 1 and Figures 2, 3 and 4, treatment of NHEK with the Oncostatin M + IL-17 + TNF-a cytokine mix dramatically increased the transcription of JAK/ STAT signaling markers, cytokines and chemokines mRNA; by 681%, 3,744% and 10,761%, respectively.

Figure 4. Treatment with 0.4% PN complex inhibited chemokine synthesis in human keratinocytes induced with a cytokine mixture; * = statistically significant.

Figure 4. Treatment with 0.4% PN complex inhibited chemokine synthesis in human keratinocytes induced with a cytokine mixture; * = statistically significant.

As shown in Table 1 and Figures 2, 3 and 4, treatment of NHEK with the Oncostatin M + IL-17 + TNF-a cytokine mix dramatically increased the transcription of JAK/ STAT signaling markers, cytokines and chemokines mRNA; by 681%, 3,744% and 10,761%, respectively.

Figure 5. Treatment with increasing doses of the EG complex inhibited NF-κB activity in human cells induced with TNF-α (20 ng/mL); * = statistically significant.

Figure 5. Treatment with increasing doses of the EG complex inhibited NF-κB activity in human cells induced with TNF-α (20 ng/mL); * = statistically significant.

This inhibition was dose-dependent (see Figure 5) and statistically significant at all concentrations used (z < 1.96, Wilcoxon test), with a max inhibition at 1.1% (-85% vs cytokine mix-induced).

Figure 6. Treatment with increasing doses of the EG complex inhibited IL-8 release in human keratinocytes induced with a cytokine mixture; * = statistically significant.

Figure 6. Treatment with increasing doses of the EG complex inhibited IL-8 release in human keratinocytes induced with a cytokine mixture; * = statistically significant.

This increase, in comparison with the untreated control NHEK, was +98.2% for IL-8 and +66.6% for CXCL1 (see Figures 6 and 7).

Figure 7. Treatment with increasing doses of the EG complex inhibited CXCL1 release in human keratinocytes induced with a cytokine mixture; * = statistically significant.

Figure 7. Treatment with increasing doses of the EG complex inhibited CXCL1 release in human keratinocytes induced with a cytokine mixture; * = statistically significant.

This increase, in comparison with the untreated control NHEK, was +98.2% for IL-8 and +66.6% for CXCL1 (see Figures 6 and 7).

Figure 8. Treatment with a water-based gel containing the EG complex at 3.0% and 1.0% reduced SLS-induced eythema on human volunteers (n = 25); * = statistically significant.

Figure 8. Treatment with a water-based gel containing the EG complex at 3.0% and 1.0% reduced SLS-induced eythema on human volunteers (n = 25); * = statistically significant.

The lowest concentration of EG complex (1.0%) reached significance (p < 0.001, t-test) after 120 min of application (see Figure 8).

Figure 9. Treatment with a water-based gel containing the EG complex at 3.0% and 1.0% reduced SLS-induced TEWL on human volunteers (n = 25); * = statistically significant.

Figure 9. Treatment with a water-based gel containing the EG complex at 3.0% and 1.0% reduced SLS-induced TEWL on human volunteers (n = 25); * = statistically significant.

At 120 min of application, the 3.0% EG complex gel reduced TEWL by 23% (see Figure 9).

Figure 10. Treatment with a cream containing the PN complex at 2.0% and 0.5% reduced SLS-induced erythema on human volunteers (n = 25); * = statistically significant.

Figure 10. Treatment with a cream containing the PN complex at 2.0% and 0.5% reduced SLS-induced erythema on human volunteers (n = 25); * = statistically significant.

Also at 120 min of application, the cream containing the 2.0% PN complex reduced the erythema index by 13% (see Figure 10).

Figure 11. Treatment with a cream containing the PN complex at 2.0% and 0.5% reduced SLS-induced TEWL on human volunteers (n = 25); * = statistically significant.

Figure 11. Treatment with a cream containing the PN complex at 2.0% and 0.5% reduced SLS-induced TEWL on human volunteers (n = 25); * = statistically significant.

At 120 min of application, the cream containing the 2.0% complex reduced TEWL by 15% (see Figure 11).

Footnotes (CT1101 G. Dell'Acqua.)

a Unisooth EG-28 (INCI: Water (aqua) (and) Gallyl Glucoside (and) Epigallocatechin Gallatyl Glucoside (and) Propyl Gallate) is a product of Induchem AG.
b Unisooth PN-47 (INCI: Panthenyl Triacetate (and) Naringenin) is a product of Induchem AG.
c pNiFty2SEAP is an alkaline phosphatase carrying plasmid manufactured by Invivogen.
d Finn chambers on scanpor are manufactured by Allergopharma–Merck Group, Germany.
e The Mexameter MX 18 is manufactured by Courage and Khazaka Electronic GmbH.
f The Tewameter 300 is manufactured by Courage and Khazaka Electronic GmbH.

Next image >