No abstract

Despite clear exacerbation of several skin disorders by stress, the effect of psychologic or exertional stress on human skin has not been well studied. We investigated the effect of three different stressors, psychologic interview stress, sleep deprivation, and exercise, on several dermatologic measures: transepidermal water loss, recovery of skin barrier function after tape stripping, and stratum corneum water content (skin conductance). We simultaneously measured the effects of stress on plasma levels of several stress-response hormones and cytokines, natural killer cell activity, and absolute numbers of peripheral blood leukocytes. Twenty-five women participated in a laboratory psychologic interview stress, 11 women participated in one night of sleep deprivation, and 10 women participated in a 3 d exercise protocol. The interview stress caused a delay in the recovery of skin barrier function, as well as increases in plasma cortisol, norepinephrine, interleukin-1beta and interleukin-10, tumor necrosis factor-alpha, and an increase in circulating natural killer cell activity and natural killer cell number. Sleep deprivation also decreased skin barrier function recovery and increased plasma interleukin-1beta, tumor necrosis factor-alpha, and natural killer cell activity. The exercise stress did not affect skin barrier function recovery, but caused an increase in natural killer cell activity and circulating numbers of both cytolytic T lymphocytes and helper T cells. In addition, cytokine responses to the interview stress were inversely correlated with changes in barrier function recovery. These results suggest that acute psychosocial and sleep deprivation stress disrupts skin barrier function homeostasis in women, and that this disruption may be related to stress-induced changes in cytokine secretion.

Langerhans cells (LC) are epidermal dendritic cells capable, in several experimental systems, of Ag-presentation for stimulation of cell-mediated immunity. LC have been considered to play a key role in initiation of cutaneous immune responses. Additionally, administration of donor T cells to bone marrow chimeric mice with persistent host LC, but not mice whose LC have been replaced by donor cells, exhibit marked skin graft-vs-host disease, demonstrating that LC can trigger graft-vs-host disease. However, experiments with transgenic mice in which regulatory elements from human langerin were used to drive expression of diphtheria toxin, resulting in absence of LC, suggest that LC may serve to down-regulate cutaneous immunity. LC are associated with nerves containing the neuropeptide calcitonin gene-related peptide (CGRP), and CGRP inhibits LC Ag-presentation in several models including presentation to a Th1 clone. We now report that CGRP enhances LC function for stimulation of Th2 responses. CGRP exposure enhanced LC Ag presentation to a Th2 clone. Upon presentation of chicken OVA by LC to T cells from DO11.10 chicken OVA TCR transgenic mice, pretreatment with CGRP resulted in increased IL-4 production and decreased IFN-γ production. CGRP also inhibited stimulated production of the Th1 chemokines CXCL9 and CXCL10 but induced production of the Th2 chemokines CCL17 and CCL22 by a dendritic cell line and by freshly obtained LC. Changes in production of these chemokines correlated with the effect of CGRP on mRNA levels for these factors. Exposure of LC to nerve-derived CGRP in situ may polarize them toward favoring Th2-type immunity.

The sympathetic nervous system modulates immune function at a number of levels. Within the epidermis, APCs (Langerhans cells (LC)) are frequently anatomically associated with peripheral nerves. Furthermore, some neuropeptides have been shown to regulate LC Ag-presenting function. We explored the expression of adrenergic receptors (AR) in murine LC and assessed their functional role on Ag presentation and modulation of cutaneous immune responses. Both purified LC and the LC-like cell lines XS52-4D and XS106 expressed mRNA for the ARs α1A and β2. XS106 cells and purified LC also expressed β1-AR mRNA. Treatment of murine epidermal cell preparations with epinephrine (EPI) or norepinephrine inhibited Ag presentation in vitro. Furthermore, pretreatment of epidermal cells with EPI or norepinephrine in vitro suppressed the ability of these cells to present Ag for elicitation of delayed-type hypersensitivity in previously immunized mice. This effect was blocked by use of the β2-adrenergic antagonist ICI 118,551 but not by the α-antagonist phentolamine. Local intradermal injection of EPI inhibited the induction of contact hypersensitivity to epicutaneously administered haptens. Surprisingly, injection of EPI at a distant site also suppressed induction of contact hypersensitivity. Thus, catecholamines may have both local and systemic effects. We conclude that specific ARs are expressed on LC and that signaling through these receptors can decrease epidermal immune reactions.

Ultraviolet radiation (UVR) promotes skin cancer development by mutagenic, immunosuppressive, and oxidative-stress-inducing mechanisms; however, certain antioxidants may counteract and prevent UVR-induced photodamage. Lutein is a xanthophyll carotenoid with potent antioxidant activity. Because reactive oxygen species (ROS) are believed to have a role in UVR-induced skin damage, we investigated whether lutein can modify UVR effects including the tissue swelling response to midrange UVR (280-320 nm, ultraviolet B (UVB) radiation) and UVB suppression of contact hypersensitivity (CHS) in both the local and the systemic models of UV-induced immunosuppression. We found that compared to mice fed the standard laboratory diet, mice fed dietary lutein demonstrated significant inhibition of ear swelling owing to UVB radiation. Mice exposed to 1700 J per m2 UVB radiation four times at daily intervals and then sensitized to dinitrofluorobenzene at the site of irradiation showed a decreased CHS response upon challenge. This suppression by UVB radiation was significantly inhibited by lutein feeding. When UVB radiation was given at a single dose of 10,000 J per m2 to inhibit the induction of CHS at a distant, nonirradiated site, no effect of lutein was seen. Finally, lutein accumulated in the skin of mice following diet supplementation and was shown to decrease ROS generation following UVR exposure. Thus, lutein modulates the skin's response to UVR and may contribute to the defense against some of the deleterious effects of solar radiation.

We have previously demonstrated that fulllength heparin stimulates the synthesis and secretion of -amyloidprecursor protein (APP) through an amyloidogenic pathway in neuroblastoma cells. In the present study, heparin was chemically depolymerized, and the effect of low-molecular-weight (LMW) hepanin on APP secretion was investigated. In contrast to full-length hepar, LMW heparin had no significant effect on APP secretion. However, LMW heparin fragments, especially hepanfl disaccharides, were able to inhibit efficiently the stimulatory effect of heparin on APP secretion. LMW heparin derivatives also inhibit the binding of heparin to the /3amyloid peptide (1-28). Using an in vitro model, we further demonstrated the passage of LMW heparin derivatives through the blood-brain barrier. This study suggests that LMW heparin derivatives or analogues may be effective as therapeutic agents to prevent or slow the process of amyloidogenesis in Alzheimer's disease.

Adenosine 5'-triphosphate (ATP) affects multiple intra- and extracellular processes, including vascular tone and immune responses. Microvascular endothelial cells (EC) play a central role in inflammation by recruitment of inflammatory cells from blood to tissues. We hypothesized that ATP (secreted by neurons and/or released after perturbation of cutaneous cells) may influence secretion of inflammatory messengers by dermal microvascular EC through actions on purinergic P2 receptors. Addition of the hydrolysis-resistant ATP analogue, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), to subconfluent cultures of the human microvascular endothelial cell-1 (HMEC-1) cell line led to a dose- and time-dependent increase in release of IL-6, IL-8, monocyte chemoattractant protein-1, and growth-regulated oncogene alpha. Both ATPgammaS-induced release and basal production of these proteins were significantly inhibited by the purinergic antagonists pyridoxal-5'-phosphate-6-azophenyl-2',5'-disulfonic acid (PPADS), pyridoxal-5'-phosphate-6(2'-naphthylazo-6-nitro-4',8'-disulfonate), and suramin. ATPgammaS increased expression of intercellular adhesion molecule-1 (ICAM-1), whereas suramin and PPADS decreased both ATPgammaS-induced and basal ICAM-1 expression. Using PCR, we found that HMEC-1 strongly express mRNA for the P2X(4), P2X(5), P2X(7), P2Y(2), and P2Y(11) receptors and weakly express mRNA for P2X(1) and P2X(3) receptors. Purinergic nucleotides may mediate acute inflammation in the skin and thus contribute to physiological and pathophysiological inflammation. For example, ATP may contribute to both the vasodilation and the inflammation associated with rosacea.

Langerhans cells (LCs) are antigen-presenting cells in the skin that play sentinel roles in host immune defense by secreting proinflammatory molecules and activating T cells. Here we studied the interaction of vaccinia virus with XS52 cells, a murine epidermis-derived dendritic cell line that serves as a surrogate model for LCs. We found that vaccinia virus productively infects XS52 cells, yet this infection displays an atypical response to anti-poxvirus agents. Whereas adenosine N1-oxide blocked virus production and viral protein synthesis during a synchronous infection, cytosine arabinoside had no effect at concentrations sufficient to prevent virus replication in BSC40 monkey kidney cells. Poxviruses are dermatotropic DNA viruses that cause human diseases ranging in severity from a mild local skin eruption (molluscum contagiosum) to a catastrophic systemic illness signaled by a generalized pustular rash (smallpox). Poxviruses employ multiple strategies to evade the immune system, including (i) secretion of virus-encoded soluble cytokine receptors or cytokine analogs that act as molecular decoys to block the activity of host cytokines and (ii) elaboration of viral antagonists of the major intracellular signaling pathways that either trigger apoptosis, establish an antiviral state, or activate proinflammatory responses (reviewed in reference 44). Vaccinia virus, the laboratory prototype for the poxvirus family, has a 200-year history of intentional human infection via the skin for the purpose of smallpox prophylaxis. The stigma of successful vaccination is a localized pustular rash that, in uncomplicated cases, heals without either spreading to adjacent areas of skin or triggering serious systemic inflammation. Major complications of vaccination such as eczema vaccinatum are more common in individuals with abnormal skin immunity (50). Life-threatening progressive vaccinia virus occurs in patients with T-cell immunodeficiency (18). Molluscum contagiosum, a normally benign and self-limited skin infection of healthy children, is either more severe or more difficult to eradicate in children with atopic dermatitis and in immunocompromised patients (13,17). These clinical correlations suggest that delineating the biology of natural poxvirus infections and the mechanisms underlying immunization via scarification (and ways to avoid or treat the complications of vaccination) would benefit from a better understanding of the interactions of poxviruses with the skin immune system.Langerhans cells (LCs) are epidermal antigen-presenting dendritic cells (DCs) that play important roles in skin immune responses (3,40). Derived from CD34 ϩ progenitor cells in the bone marrow (28), they establish their residence in the basal and suprabasal layers of the epidermis. Whereas LCs in noninflamed skin are maintained by skin-resident hematopoietic precursors that self-renew in situ, skin injury results in loss of resident LCs and their replacement by circulating monocyte precursors (19,36). LCs in the epidermis are immature, though capa...