From the Department of Dermatology,
Boston University School of Medicine, Boston, Massachusetts
American Journal
of Pathology, Vol. 162, No. 3, March 2003 Copyright © American Society for
Investigative Pathology.
Accepted for publication December 23, 2002.
Address reprint requests to Vladimir A. Botchkarev, M.D., Ph.D., Department
of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA
02118. E-mail:
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All living organisms are constantly challenged by a
diversity of exogenous (environmental, psychological, social) and endogenous
stimuli or stressors, which induce general or local biological responses to
protect or adapt the organism to the stressor(s).1 The systemic
biological response of the organism to exogenous stressors (or classical stress
response) includes activation of the hypothalamic- pituitary-adrenal axis and
release of hypothalamic corticotropin-releasing hormone (CRH) that activates
pituitary CRH receptors (CRH-R) followed by the production and release of
proopiomelanocortin-derived peptides and adrenal hormones.2,3
Systemic stress response also includes the modulation of the autonomic nervous
and immune systems: neuroendocrine hormones and neurotransmitters influence the
function of the immune system that reciprocally regulate CNS functions through
cytokine release.4
Skin as a Target for Systemic and Local Stress ResponsesSkin is an
organ that covers and protects body from environmental (physical, chemical, or
biological) stressors, which include temperature, ultraviolet radiation,
mechanical trauma, biological insults, and chemicals. Skin is richly innervated
by sensory nerves5,6 that transmit information about the effects
caused by environmental stressors to the central nervous system to develop the
systemic response of the organism appropriate to its external environment. In
turn, the hormones secreted during the systemic stress response and
neurotransmitters of the autonomic nerve fibers innervating skin may target skin
cells and modulate or affect their functions, depending on circumstances.7
Data obtained during the last decade suggest that the major molecular
components that mediate the systemic response to environmental stressors (CRH
and proopiomelanocortin peptides), as well as neurotransmitters and cytokines
are also expressed in the skin.7–10 Specifically, it is shown that
epidermal keratinocytes, fibroblasts, mast cells, and immune cells express
CRH-R1, whereas CRH protein is expressed in keratinocytes and dermal nerve
fibers.11,12 The proopiomelanocortin peptides (ACTH, -MSH,
-endorphin) have also been detected in keratinocytes, melanocytes, and
Langerhans cells.13–17 Neurohormones, cytokines, and
neurotransmitters secreted by the major structural components of the skin
(keratinocytes, melanocytes, fibroblasts, immune and endothelial cells, nerve
fibers) form a molecular network of signals that is activated during cutaneous
response to different environmental stimuli.10 Therefore, together
with the systemic stress response, environmental stressors may also induce the
stress response inside of the skin, which may operate as a local equivalent of
the hypothalamic-pituitary- adrenal axis.10
Numerous indications suggest that both systemic and local responses to
stressors may have roles in the onset or exacerbation of a variety of skin
diseases.18 Psychological stress is now considered as an important
etiological factor in the onset of psoriasis, atopic dermatitis, pruritus, and
urticaria.18 Sensory neuropeptides and neurotransmitters released by
sensory and autonomic nerve fibers that innervate the skin can directly modulate
functions of keratinocytes, melanocytes, Langerhans cells, mast cells,
endothelial cells, and immune cells.15,19–21 Among the molecules
substance P, calcitonin gene-related peptide, vasoactive intestinal peptide,
somatostatin, noradrenaline, and acetylcholine have been reported to effectively
modulate skin and immune cell functions such as cell proliferation, cytokine
production, or antigen presentation under normal and pathological
conditions.15,19–22 This further proves the concept that skin serves
as an important target for systemic and local stress responses.
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