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. |
