Re: Skin as an endocrine organ/ Being ZEN with KEN & SKIN?
randall
> archive: yes
>
> http://tinyurl.com/yytecwm
>
> Common skin conditions and disorders
>
> Skin as an endocrine organ: implications for its function
>
> Andrzej Slominski1, , , Jacobo Wortsman2, Ralf Paus4, Peter M. Elias3,
> Desmond J. Tobin5 and Kenneth R. Feingold3
> 1Department of Pathology and Laboratory Medicine, University of
> Tennessee HSC, Memphis, TN, USA
> 2Department of Medicine, Southern Illinois University, Springfield, IL, USA
> 3Department of Dermatology, VA Medical Center, San Francisco, CA, USA
> 4Department of Dermatology, University of Luebeck, Luebeck, Germany
> 5Centre for Skin Sciences, School of Life Sciences, University of
> Bradford, West Yorkshire, UK
>
> Available online 13 May 2008.
> Described as the body's largest organ, the skin is strategically located
> at the interface with the external environment where it has evolved to
> detect, integrate and respond to a diverse range of stressors. A flurry
> of recent findings has established the skin as an important peripheral
> (neuro)endocrine organ that is tightly networked to central stress axes.
> This capability is contributing to the maintenance of body homeostasis,
> and in this way could be harnessed for therapeutic strategies.
> Section editor:
> Michael Roberts – School of Medicine, University of Queensland, Australia
> Article Outline
>
> Introduction
> Effect of psychological stress (PS) on skin (Fig. 1)
> Cutaneous expression of CRF signaling system
> CRF regulates cutaneous POMC expression and production of POMC peptides
> Cutaneous steroidogenesis
> Cutaneous HPA axis (Fig. 2)
> Summary and conclusions
> Acknowledgements
> References
Susan,
Shall we do it, some more?
I mean more of your topic?
Like pomc and crf and things that go bumP?
And beside skin being endocrine so is the stomach.
Right uP our ALLEY perhaPs for this thread?
Let's see the skinny on KR Feingold.
We must have at least a few feingold abstracts in the P nG?
Nope> not seeing any in the group.
Manfred did post a Feingold SKIN is endocrine article from 2006:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/browse_thread/thread/fa0742b307285db5/fb6f11cd2a8e8dfa?hl=en&q=Feingold+skin+largest+organ+psoriasis
I guess at this point we see how smart Ken Feingold is?
Will skin smartyness from Ken translate to action in the psor support
group?
Is it as simPle as being ZEN and sitting in the SUN shine?
OK..
He's got, got, got...
398 Abstracts on pubmed:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Feingold%20KR%22%5BAuthor%5D
The study you cite is 14 (Jun/2008) since the MOST recent.
Yet the Most recent has no meat in the taco:
http://www.ncbi.nlm.nih.gov/pubmed/20376063
Feingolds' second most recent deals with my PET : LPS (endotoxin)
http://www.ncbi.nlm.nih.gov/pubmed/20100709
Innate Immun. 2010 Jan 25.
Endotoxin, zymosan, and cytokines decrease the expression of the
transcription factor, carbohydrate response element binding protein,
and its target genes.
Feingold KR, Shigenaga JK, Patzek SM, Chui LG, Moser A, Grunfeld C.
Abstract
Carbohydrate response element binding protein (ChREBP) is a recently
discovered transcription factor whose levels and activity are
increased by glucose leading to the activation of target genes, which
include acetyl-CoA carboxylase, fatty acid synthase, and liver-type
pyruvate kinase. Here, we demonstrate that lipopolysaccharide (LPS)
treatment causes a marked decrease in ChREBP mRNA and protein levels
in the liver of mice fed a normal chow diet or in mice fasted for 24 h
and then re-fed a high carbohydrate diet. This decrease occurs rapidly
and is a sensitive response (half-maximal dose 0.1 mug/mouse). The
decrease in ChREBP is accompanied by a decrease in the expression of
ChREBP target genes. Zymosan and turpentine treatment also decrease
hepatic ChREBP levels and the expression of its target genes.
Additionally, tumor necrosis factor alpha (TNF-alpha) and
interleukin-1 beta (IL-1beta) decrease liver ChREBP expression both in
vivo and in Hep3B cells in culture. Finally, LPS decreased ChREBP
expression in muscle and adipose tissue. These studies demonstrate
that ChREBP is down-regulated during the acute phase response
resulting in alterations in the expression of ChREBP regulated target
genes. Thus, ChREBP joins a growing list of transcription factors that
are regulated during the acute phase response.
PMID: 20100709
Whatz ChREBP?
110 hits on pubmed and nada on wikipedia:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ChREBP
The MOST recent being salient to the PSOR SKIN at hand?
And brings sugars and genes (Mlx) in to our psoriatic pathways you can
only speculate. LOL
[randall note: leucine zipper MLX -http://en.wikipedia.org/wiki/
MLX_(gene) ]
http://www.ncbi.nlm.nih.gov/pubmed/20382893
ChREBP and LPS in situ (skin & FAT) certainly are as interesting as
EG's? To myself fur sure!
http://en.wikipedia.org/wiki/In_situ#Medicine
(LPS and carby binding protein versus a tumor brings us back to
Th1 versus Th2 skewing-ness and the ultimate relationship to the GUT
track, shall we find that
as the etiological point of orgins?)
To wit:
http://en.wikipedia.org/wiki/Endocrine_gland
Hey i'm not seeing any skin ON this page??
Wait, wait....
OK, way down the page to:
http://en.wikipedia.org/wiki/Endocrine_gland#Other_hormone-producing_structures
So obviously that which makes the skin an endocrine organ is the
ability to produce cholecalciferol (vitamin D3).
And oral suPPlemented D3 in food would make the stomach an
endocrine organ???
http://en.wikipedia.org/wiki/Cholecalciferol
And since fat (adipose tissue) lives in the skin:
thusly
we have : adipose tissue (leptin and resistin).
http://en.wikipedia.org/wiki/Adipose_tissue
http://en.wikipedia.org/wiki/Leptin
http://en.wikipedia.org/wiki/Resistin
to
http://en.wikipedia.org/wiki/Resistin#Inflammation
And to my SWEET wHEY of thinking i wouldn't leave
leptin resistance out of these pathways (inflammatory and psoriatic
ones).
http://en.wikipedia.org/wiki/Lectin#Lectin_and_Leptin_Resistance
OK and back to the abstract for Skin as Endocrine:
http://www.ncbi.nlm.nih.gov/pubmed/19492070
Drug Discov Today Dis Mech. 2008 Jun 1;5(2):137-144.
Skin as an endocrine organ: implications for its function.
Slominski A, Wortsman J, Paus R, Elias PM, Tobin DJ, Feingold KR.
Department of Pathology and Laboratory Medicine, University of
Tennessee HSC, Memphis, TN, USA.
Abstract
Described as the body's largest organ, the skin is strategically
located at the interface with the external environment where it has
evolved to detect, integrate and respond to a diverse range of
stressors. A flurry of recent findings has established the skin as an
important peripheral (neuro)endocrine organ that is tightly networked
to central stress axes. This capability is contributing to the
maintenance of body homeostasis, and in this way could be harnessed
for therapeutic strategies.
PMID: 19492070
And instead of registering at elsevier to view it. As the option on
your
tinyurl link provides...
It's right here: [on pubmed in it's entirety]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658605/?tool=pubmed
Introduction
Skin function is a crucial component of organismal survival [1,2]. The
skin acts as physical barrier separating the biological milieu from
the environment [1], a function that requires precise calibration of
cutaneous responses, and a high degree of local autonomy [2]. To that
end, it has developed sophisticated sensory, computing and signaling
systems to differentially respond to environmental changes represented
by biological, chemical, physical or electromagnetic (wide spectrum of
wavelengths of solar radiation) factors, and to signal to distant,
extracutaneous cells and organs in the mammalian body. The
corresponding cutaneous responses are addressed at protecting,
restoring or maintaining the optimal body homeostassis [2]. These
highly localized responses are coordinated partly by a skin
neuroendocrine system that is able to reset adaptation mechanisms
through rapid (neural) or slow (humoral) pathways acting at local or
systemic levels [2–4].At the systemic level, the main central
regulator of responses to perceived stress is the hypothalamic–
pituitary–adrenal (HPA) axis, where activation follows a sequential
pattern starting from the release of corticotropin releasing factor
(CRF), and involving CRF receptor 1 (CRF1), pro-opio-melanocortin
(POMC) and adrenal glucocorticoids synthesis/release; the axis is also
modulated by cytokines [5,6]. The same axis is also expressed in the
skin, where it represents an important component of the local response
to cutaneous stress [4,7].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658605/figure/F1/
PS has been associated with exacerbation and propagation of cutaneous
disorders such as psoriasis, atopic dermatitis, delayed wound healing,
and risks of infections or recurrence of HSV and H. Zoster [8]. Skin
disorders adversely affected by PS are frequently characterized by
defective cutaneous permeability barrier function. The potential
importance of barrier function is supported by the discovery that
atopic dermatitis may be caused by mutations in the filaggrin gene
allowing sustained antigen ingress, eliciting a characteristic TH2
immune response [9].Recent studies have shown that PS compromises
permeability barrier function in rodents and humans [10–13]. PS
decreases epidermal proliferation and the expression of
differentiation markers, such as involucrin, loricrin, and filaggrin,
leading to a thin epidermis, and defective corneocytes [14]. PS also
reduces the density and secretion of lamellar bodies (LBs) impairing
barrier function [14]. PS reduces epidermal cholesterol, fatty acid,
and ceramide synthesis and the topical application of lipids restores
barrier recovery kinetics to normal in PS animals [14].Adhesion
between adjacent corneocytes is facilitated by corneodesmosomes (CD)
(specialized desmosomes of the SC), which rivet together adjacent
cells, and by extracellular lipids. Detachment of adjacent corneocytes
begins with the progressive, proteolytic degradation of the e-
cadherins, DSG1 and DSC1, as well as a unique CD-coating protein,
corneodesmosin in the lower SC (stratum compactum). This process is
impaired by PS (decreased stratum corneum integrity and cohesion)
[14]. Topical applications of exogenous lipids also normalize stratum
corneum integrity in PS mice [14].Systemic and topical GC treatment
produce abnormalities in epidermal structure and function in mice
virtually identical to those observed in PS [15]. GC decrease
epidermal proliferation and differentiation (epidermal thinning or
atrophy) and impair permeability barrier homeostasis and SC integrity
and cohesion [15]. Similar to PS, GC treatment decreases epidermal
lipid synthesis, reduces LB formation, extracellular lamellar
membranes and density of CD in SC [15]. Conversely, as in PS animals,
topical application of a mixture of barrier lipids largely corrects
the GC-induced abnormality in permeability barrier homeostasis and the
abnormal SC integrity and cohesion but did not correct the abnormality
in either keratinocyte proliferation or differentiation [15]. Thus, GC
could mediate the abnormalities in epidermal function produced by
PS.PS stimulates the HPA axis activity with an increase in secretion
of the hypothalamic hormone, CRF leading to increased ACTH secretion
and adrenal GC production [5,6]. Both inhibition of GC action with
RU-486 or pharmacological inhibition of CRF1 with antalarmin prevented
the development of PS-induced abnormalities in epidermal structure and
function in the face of ongoing PS [16]. GC inhibition restores
epidermal lipid synthesis and LB formation/secretion, as well as the
density of CD in PS animals, supporting GC as the mediator for the PS-
induced abnormalities [16].The barrier to pathogenic microbes is
composed of surface-deposited free fatty acids and AMPs, as well as an
intact (cohesive) structurally normal SC [17]. Additionally, the low
water content of the intact SC and SC pH of 5.5 encourages the growth
of benign bacteria while inhibiting the growth of pathogens [17].
Additionally, AMPs and amphilic lipids, particularly sphingosine and
free fatty acids, decrease the growth of microbes [17].PS modulates
epidermal AMP levels by reducing CRAMP and mBD3 (the closest murine
homologs of LL-37 and hBD2, respectively) protein levels [18]. PS also
reduces the delivery of AMPs to LB [18]. Moreover, the decrease in
CRAMP is because of a decrease in gene transcription while the
decrease in mBD3 is due to post-translational effects [18].Systemic or
topical GC also decreases CRAMP and mBD3 protein levels in the
epidermis [18]. Endogenous GC are probably to account for the PS-
induced decline in AMP levels. In the face of ongoing PS, treatment
with inhibitors of GC production or action normalizes epidermal
protein levels for both CRAMP and mBD3 [18]. Furthermore,
adrenalectomy increases the constitutive expression of both AMPs
[18].Co-administration of a mixture of ceramides, cholesterol, and
free fatty acids, at a ratio designed to correct the PS/GC-induced
inhibition of epidermal lipid synthesis also normalizes mBD3 in PS
[18]. The ability of topical lipids to correct the decrease in mBD3 is
consistent with post-transcriptional regulation of this AMP by PS/
GC.PS increases susceptibility to cutaneous infections in a GC-
dependent fashion [18]. Similar to CRAMP knock-out mice, PS increases
susceptibility to group A streptococcus skin (GAS) infections,
consistent with the reduction of CRAMP levels [18]. Thus, PS has
negative consequences for resistance to cutaneous GAS infections,
presumably owing to reduced CRAMP and mBD3 expression.In conclusion,
PS, acting via GC, inhibits keratinocyte
Cutaneous expression of CRF signaling system
Human skin expresses the genes for CRF, urocortins 1−2 (URC1, URC2)
and produces the corresponding peptides as documented by RP-HPLC, mass
spectrometry (MS) and immunocytochemistry analyses [19,20]. In human
skin or hair follicles (in situ) and/or in cultured human skin cells,
the expression of the CRF and production of CRF are stimulated by
ultraviolet (UV) radiation and forskolin, and are inhibited by
dexamethasone and cortisol [19–21]. Mouse skin also contains
fluctuating amounts of CRF peptide (whose concentration actually
changes in a hair cycle-dependent fashion), while corresponding CRF
transcripts have not yet been documented in situ, suggesting that
murine skin CRF may arise from an extracutaneous source, for example,
local nerve endings [20,22]. Also in mice URC1 production is hair
cycle-dependent, albeit in a pattern opposite to that of CRF, whereas
URC2 mRNA was detected in the epidermal and dermal compartments of the
skin of humans and rodents [19,23]. Cutaneous production of CRF and
urocortins appears to be highly compartmentalized, and given the
diverse phenotypic effects of the peptides, mechanisms to achieve
selectivity in the activation of distinct signal transduction pathways
are probably to be operative [19,20].One such mechanism may result
from species- and cell type-specificity in the intracutaneous
expression of functional CRF1 and CRF2 [19,23], and/or by alternative
splicing of the corresponding transcripts [19,24]. Indeed, selectivity
for pleiotropic effects of CRF or URC can be modulated by differential
expression of the CRF1 isoforms, particularly the membrane bound and
soluble variants [19,23,25]. In human skin, there appears to be
exclusive expression of CRF1 in the epidermis with CRF1α being the
most prevalent isoform; CRF2 is only expressed in hair follicle
keratinocytes and papilla fibroblasts, sebaceous and eccrine glands,
muscle and dermal blood vessels [23]. In mouse skin, both CRF1 and
CRF2 are widely expressed in all cutaneous compartments [23].In
cultured human keratinocytes (normal and immortalized) CRF- and URC1-
inhibited cell proliferation, while stimulating keratinocyte cell
differentiation [19,26]; they also modulate expression of cell surface
adhesion molecules and induce or inhibit cytokines production
[19,27,28]. CRF1 and CRF2 are also expressed on sebaceus glands where
CRF can stimulate steroididogenic and secretory activities of
sebocytes [29]. CRF can also regulate skin function via activation of
mast cells expressing CRF receptors [30,31], and participate in the
regulation of hair follicle growth and pigmentation [19,32]. These
phenotypic effects are mediated by intracellular concentrations of
cAMP, IP3, Ca or NF-kappaB activity [19,33]. Overall, the additional
non-endocrine-related actions of CRF and related peptides define these
peptides as growth factors/pleiotropic cytokines that are capable of
regulating proliferation, apoptosis, differentiation, and immune
interactions in vivo [19,33].
<snip>
References CRF regulates cutaneous POMC expression and production of
POMC peptides
[randall note: http://en.wikipedia.org/wiki/POMC ]
Human and rodent skin do express POMC gene and its protein, and
further process it to final POMC peptides that include β-LPH, ACTH, α-
MSH and β-endorphin [7]. Production and release of these peptides and
the POMC precursor occur in cultured skin cells, skin tissue and hair
follicle [7]. Of note, at least in mouse skin the POMC gene is
alternatively spliced with production of truncated forms [34], also
the skin contains the full machinery necessary for POMC processing
(PC1, PC2 convertasese, and 7B2 protein) [35,36].POMC peptides
interact with MC1, MC2, MC5 and opiate receptors to regulate skin and
hair pigmentation, adnexal function, skin immune activity,
keratinocytes and fibroblasts activities including those related to
differentiation, proliferation and secretory responses [7,36–39].
Although MC2 gene is also expressed in the skin its role in phenotypic
actions awaits elucidation [34,40]. There is evidence that the UVB-
induced melanogenesis can at least partially be mediated by the
upregulation of MC receptors [41,42]. UVR is extremely important
determinant of the expression of POMC and production of its peptides
and receptors [7,41–43]. In mice expression of MCR1 is hair cycle
dependent, highest expression during anagen and the lowest during
telogen and catagen, while MC2R expression is constant through the
cycle [34].In epidermal melanocytes, dermal fibroblasts, and hair
follicles ex vivo CRF stimulates POMC gene transcription and
translation with production of ACTH via cAMP-dependent pathway(s)
[21,44,45]. The time and dose dependence of this stimulation required
activation of CRF1 and was cell type specific. CRF also stimulates α-
MSH production and extracellular release of MSH and its POMC
precursor, which also act as regulators of melanocyte differentiation
program [46]. Interestingly glucocorticoids and some growth factors
can inhibit CRF and/or POMC expression in human and mouse skin
[19,21,34,36], while POMC expression in murine skin is coupled to the
elusive biological clock mechanism regulating hair cycling [34,47].
<snip>
ReferencesCutaneous steroidogenesis
Mammalian skin expresses steroidogenically functional CYP11A1 system
[48,49]. Skin cells also express alternatively spliced isoforms of
CYP11A1 and cholesterol transport protein MLN64 [48]. Moreover,
isolated mitochondria from skin cells can transform cholesterol to
pregnenolone and progesterone, though with low efficiency, whereas 22R-
hydroxycholesterol is transformed to pregnenolone [48] or 17OH-
pregnenolone in cultured skin cells [49].The genes involved in the
sequential metabolism of pregnenolone to corticosteroids, including
3bHSD, cytochromes P450c17, and P450c21 gene are also expressed in the
skin [4,40,49]. Functional activity for these enzymes has been clearly
demonstrated in cell extracts and cultured skin cells. Thus, rapid
metabolism of progesterone and deoxycorticosterone (DOC) has been
shown in rat skin, melanoma cells and immortalized HaCaT keratinocytes
[50–52], whereas in cultured melanoma cells progesterone is
sequentially converted to DOC and further to 18OHDOC and
corticosterone but not aldosterone [50]. HaCaT keratinocytes rapidly
metabolize progesterone and DOC but to products different from
corticosterone, aldosterone and cortisol [52]. Cortisol production has
been shown in human hair follicle [21], while production of
corticosterone and cortisol in cultured normal melanocytes and
fibroblasts [4,44,45,53]. Therefore, the adrenocortical steroidogenic
pathway appears to be fully expressed in human skin at the cellular
level raising the possibility of intra-, auto or paracrine modes of
action [4].Of further significance is the capability of the cytochrome
P450scc to efficiently use substrates other than cholesterol, such as
7-DHC, ergosterol, and vitamins D2 and D3 to produce steroidal 5, 7-
dienes or hydroxyderivatives of vitamin D or ergosterol [48,54–57].
Lastly, local expression of P450scc in the skin could explain the
epidermal accumulation of 22OH-cholestrol, which possibly may play a
role in the cutaneous barrier.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658605/figure/F2/
The expression in the skin of molecular elements of the HPA axis
(POMC, CRF, CRF1 and steroidogenic activity including cortisol
production) clearly indicates biological significance [2,4,7,19].
Expression of these elements is organized into functional, cell type-
specific regulatory loops with a structural hierarchy similar to that
found in the central HPA axis [4]. Indeed, the melanocytes respond to
CRF with enhanced production of cortisol and corticosterone depending
on POMC activity and cortisol production is also stimulated by ACTH or
raises in cAMP levels [45]. Dermal fibroblasts respond to CRF and ACTH
with enhanced production of corticosterone only [44]; though cortisol
is produced constitutively in these cells [53]. In ex vivo cultures of
human hair follicles CRF or ACTH stimulates cortisol accumulation in
keratinocytes of the outer root sheath of the human scalp hair
follicle, and secretion into the media [21]. Most interestingly,
hydrocortisone treatment of isolated hair follicles is associated with
down-regulation of CRF1 in the hair follicle outer root sheath,
mirroring the central feedback control of the HPA axis ([21]; Fig.
2).These observations suggest CRF-driven responses differentially
separated to defined stresses affecting cutaneous cell populations or
tissue compartments [4,19]. These properties are displayed most
clearly by neural crest-derived melanocytes and hair follicles, whose
activation sequences and regulatory loops closely reproduce the basic
features of the central HPA axis (Fig. 2).
<sniP>
ReferencesSummary and conclusions
The complex expression of a local HPA axis in the skin and local
steoridogenic/secosteroidogenic activities must serve important
cutaneous functions. For example, by modulating physical barrier it
would provide protection from the responses to chemical and physical
insults, and will build antimicrobial and immune activities as well as
organize and coordinate the elaborate set of responses to solar
radiation at the local and systemic levels. Thus, deregulation of the
above coordinating activities could participate in the pathogenesis of
conditions such as malignant and benign hyperpoliferations, pigmentary
disorders, inflammatory dermatoses and dysfunction of adnexal and
vascular structures. Current investigations are actively pursuing the
effector functions of CRF1 and 2 agonists and antagonists in the
regulation of keratinocyte, melanocyte, sebocyte, fibroblast and
immunocytes activities (Box 1). Therapeutic targets for CRF receptors
agonists/antagonists include psoriasis, inflammatory disorders,
alopecia, vitiligo, acne, rosacea as well as solar keratosis,
epidermal cancers and melanoma (Box 1). The recently described
function and activity of CRF as a growth factor/pleiotropic cytokine
implicates differential expression of isoforms of CRF1, and precise
coupling to different signal transduction pathways.
Box 1. Related articles on CRF receptors antagonist/agonists
<snip>
Given the common ectodermal origin shared by brain and epidermis, it
is possible that the HPA axis may have originated in the integument
with primordial actions of regulating the protective mechanisms
released by environmental insults ([58]; Fig. 3). Most important may
have been protection against UVR (Fig. 4, Box 2) and antimicrobial
barrier functions subjected to regulations and fine-tuning by the
primordial HPA, because of the close association of its elements.
Under evolutionary pressure, this autoregulatory circuitry may have
undergone specialization and separation becoming detached from its
point of origin and acquiring new functions and location (i.e. CNS,
endocrine glands, immune system), while retaining its cutaneous
inhibitory activities through action of cortisol/corticosterone (Fig.
3). In this context, the retained cutaneous HPA may serve as an
evolutionary record of the parental system. Systemic consequences of
this process could underlie the effects of psychological stress-
mediated activation of central HPA axis affecting protective and
antimicrobial skin barrier functions [18]. This concept potentially
leads to therapeutic implications such as the use of systemic or
topical selective receptor antagonists for peptide and steroidal
messengers of the HPA axis, topical stimulators of cortisol metabolic
inactivation and inhibitors of steroidogenesis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658605/figure/F3/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658605/figure/F4/
Box 2. Role of the skin in the regulation of adrenal cortex activity
To understand the mechanism(s) involved in the detection and
transformation of UVR spectrum of solar radiation into an organized
systemic biological response, we have looked for an analogy with the
structure of the HPA axis [59]. Our current hypothesis is that global
(entire organism) response to UV originates in the skin and it
involves multiple pathways encompassing simultaneously the local
production of humoral messages and activation or sensory receptors
(Fig. 4). Hence, signals generated by the skin are either delivered by
ascending nerve routes to the brain or by circulation to hypothalamus,
pituitary or adrenal gland. Thus, stress (UV) would stimulate
production and secretion of glucocorticoids via sequential or
alternative modes of action originating in the skin, for example,
neural transmission to the brain versus humoral activation of either
hypothalamus, pituitary or adrenal cortex. These will depend on the
wavelength and dose of solar electromagnetic energy as well as on skin
anatomy/histology.
It is still unclear how cutaneous POMC processing differs from the
CNS, particularly in relation to PC1, PC2 and 7B2 expression. This
information is critical to elucidate the nature of the activity of
secretory products. For example, if ACTH were to predominate, one
would expect that its stimulation of cortisol production would prevail
[4], and the phenotypic effects would be represented by local
immunosuppression. If instead, if it were α-MSH, stimulation of
melanin pigmentation should represent the main local phenotypic effect
[37]. The same would apply to β-endorphin, that not only has pro-
melanogenic activity but also participates in nociception; (opioid
receptors have been identified in epidermal skin cells and nerve
endings) [3,38,39].As regards the skin steroidogenic activity the
pathway generating 5,7-steroidal dienes and their secosteroidogenic
products is probably to be expressed in human skin (an important
repository of the 7-dehydrocholesterol (7-DHC) [48]. The unsaturated B
ring of 7-DHC is, in turn, prone to breakage by UVB photons producing
vitamin D3, and analogous photolytic effects on molecules as 7-
dehydropregnenolone and/or its hydroxyderivatives (originating from
local synthesis or delivery by the circulation) could generate
secosteroidal vitamin D-like (vitDL) products [48]. This concept has
implications in therapeutic modalities for skin diseases, and the
definition of newer neurohormonal or immunomodulatory activities for
steroidal 5,7-dienes and/or their secosteroidal derivatives [48] or
new vitamin D2 and D3 hydroxyproducts [54,55,57]. Finally, the
stressed skin may modify body homeostasis by stimulation of adrenal
cortex (Fig. 4, Box 2).
Acknowledgements
We are most grateful to Drs T. and N. Ito for preparing Fig. 2 (based
on Ref. [21]) and Dr Jean Rivier for his comments on CRF1 antagonists.
Writing of this review was supported partly by NIH grants # AR052190
(AS), AR047079 (AS and DT), AR049932 (KRF), and by a grant from DFG to
RP (Pa 345/11-2).
<snip>
============================
randall.... what does it MEAN? ZEN SKIN is CLEARly obtainable via the
WHEY?
JRStern
J.