Death receptors in cutaneous biology and disease.
Death receptors are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Expression and signaling by death receptors and their respective ligands is a tightly regulated process essential for key physiologic functions in a variety of organs, including the skin. Several death receptors and ligands, Fas and Fas ligand being the most important to date, are expressed in the skin and have proven to be essential in contributing to its functional integrity. Recent evidence has shown that Fas-induced keratinocyte apoptosis in response to ultraviolet light, prevents the accumulation of pro-carcinogenic p53 mutations by deleting ultraviolet-mutated keratinocytes. Further- more, there is strong evidence that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of toxic epidermal necrolysis, acute cutaneous graft versus host disease, contact hypersensitivity and melanoma metastasis. With these new developments, strategies for modulating the function of death receptor signaling pathways have emerged and provided novel therapeutic possibilities. Specific blockade of Fas, for example with intravenous immunoglobulin preparations that contain specific anti-Fas antibodies, has shown great promise in the treatment of toxic epidermal necrolysis and may also be useful in the treatment acute graft versus host disease. Likewise, induction of death signaling by ultraviolet light can lead to hapten-specific tolerance, and gene transfer of Fas ligand to dendritic cells can be used to induce antigen specific tolerance by deleting antigen-specific T cells. Further developments in this field may have important clinical implications in cutaneous disease. (+info)
Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPARalpha activators restores tissue homeostasis.
We recently showed that topically applied PPARalpha activators promote epidermal differentiation in intact adult mouse skin. In this study we determined the effect of clofibrate and Wy-14,643, activators of PPARalpha, on hyperproliferative epidermis in hairless mice, induced either by repeated barrier abrogation (subacute model) or by essential fatty acid deficiency (chronic model). The hyperproliferative epidermis was characterized by an increased number of proliferating cells expressing proliferating cell nuclear antigen. Topical treatment with PPARalpha activators resulted in a substantial decrease in epidermal hyperplasia in both the subacute and chronic models of hyperproliferation. Following topical treatment, proliferating cell nuclear antigen-expressing cells were restricted to the basal layer, similar to normal epidermis. In hyperproliferative epidermis there was decreased expression of involucrin, profilaggrin-filaggrin, and loricrin as assayed by in situ hybridization and immunohistochemistry. Following topical treatment with PPAR activators staining for these mRNAs and proteins increased towards normal levels. Finally, topically applied clofibrate also increased apoptosis. This study demonstrates that topical PPAR activators have profound effects on epidermal gene expression in hyperproliferative skin disorders. Treatment with PPARalpha activators normalizes cell proliferation and promotes epidermal differentiation, correcting the cutaneous pathology. This study identifies PPARalpha activators as potential skin therapeutic agents. (+info)
Changes in tactile spatial discrimination and cutaneous coding properties by skin hydration in the elderly.
Neurosensory tactile functions were investigated in human subjects by two different and complementary experimental approaches. First, a conventional psychophysical method (two-point gap discrimination) was used to determine the tactile discrimination threshold by analyzing the subjects' ability to detect a gap of variable width between two contact points when a series of stimuli was applied to the skin. Using this method we confirmed the marked degradation of tactile spatial acuity with age and showed that skin discriminative function was partially restored after hydration of the skin with a moisturizer. The second approach consisted of a microneurographic recording of tactile afferent fibers in response to two types of mechanical stimuli applied reproducibly to the corresponding receptive fields. With this method, we found that the afferent messages were depressed following hydration of the skin surface. Thus, partial restoration of tactile spatial acuity after hydration appears to be due to both a softening of the stratum corneum permitting better localization of the stimulus and a weaker transfer of the stimulus toward the sensory receptors. (+info)
Leukemia inhibitory factor induces epidermal hyperplasia in patients with amyotrophic lateral sclerosis.
We investigated the biochemical and morphologic alteration in skin of amyotrophic lateral sclerosis patients. We found an obvious high expression of leukemia inhibitory factor and distinct epidermal hyperplasia in the skin of amyotrophic lateral sclerosis patients compared with disease controls. The thickness and cell density, as well as the leukemia inhibitory factor immunostain density, of the epidermis in amyotrophic lateral sclerosis patients correlated positively with duration of illness. The striking fact was the significant epidermal hyperplasia correlating with leukemia inhibitory factor expression in amyotrophic lateral sclerosis patients (r = 0.94, p < 0.001). In vitro experiments revealed that leukemia inhibitory factor stimulated keratinocyte proliferation in primary keratinocyte culture and induced epidermal hyperplasia in skin organ culture. These findings lead to the hypothesis that a high expression of leukemia inhibitory factor is closely associated with epidermal hyperplasia in amyotrophic lateral sclerosis patients. (+info)
Expression of a retinoid-inducible tumor suppressor, Tazarotene-inducible gene-3, is decreased in psoriasis and skin cancer.
Tazarotene-induced gene-3 (TIG-3), isolated from human keratinocytes treated with the retinoic acid receptor-selective retinoid Tazarotene, is homologous to H-rev, a class II tumor suppressor. TIG-3 gene localized to chromosome 11q23, a site of loss of heterozygosity in several malignancies. Retinoids influence epidermal differentiation and are used to treat and prevent skin cancer. Therefore, we studied TIG-3 mRNA expression in psoriasis and in basal and SCCs by in situ hybridization and a quantitative QT-RT-PCR assay. Psoriasis lesions had significantly lower staining (median, 3) than paired normal control skin (median, 4; P = 0.012). TIG-3 mRNA was significantly higher in normal control skin (P = 0.001), in paired adjacent skin (median, 3; P = 0.007), and in overlying epidermis (median, 3.0; P = 0.0001) than in 21 SCC specimens as a group (median, 1.5). (+info)
Histological studies of pedicle skin formation and its transformation to antler velvet in red deer (Cervus elaphus).
Deer antlers and their antecedent pedicles are made up of two components, interior osseocartilage and exterior integument. In a previous study, we described that histogenesis of the interior osseocartilage proceeds through four ossification stages. These are intramembranous (IMO), transition (OPC), pedicle endochondral (pECO), and antler endochondral (aECO). In the present study, we used histological techniques to examine pedicle skin formation and its transformation to antler velvet. The results showed that pedicle skin initiated from the apex of a frontal lateral crest and was formed through three distinctive stages. These stages are 1) compression of the subcutaneous loose connective tissue at the OPC stage, 2) stretching of the undulated epidermis at the early pECO stage, and 3) neogenesis of the skin and its associated appendages at the mid pECO stage. Transformation into antler velvet, which occurs at the late pECO stage, is mainly associated with alteration in the skin appendages. This alteration includes the loss of arrector pili muscle and sweat glands, and the gain of the large bi- or multi-lobed sebaceous glands. These results suggest that pedicle skin expansion occurs to release the mechanical tension created by underlying forming antlerogenic tissue, initially in response to it by mechanical stretch, and then by neogenesis of skin. In turn, the stretched pedicle skin may exert mechanical pressure on the underlying antlerogenic tissue causing it to change in ossification type. Antler velvet generation may be accomplished by both mechanical stimulation and chemical induction from the underlying pECO stage antlerogenic tissue. If this hypothesis is correct it is likely that mechanical stimulation would drive skin formation and chemical induction then determine skin type. Furthermore, asynchronous transformation of the interior and exterior components during pedicle formation and antler generation may result from the delayed chemical induction and the way antler velvet initially generates. The results from both mitotic cell labelling of the basal layer and ultrastructure of the basement membrane of the apical skin in the study support these hypotheses. (+info)
Patterns of hairless (hr) gene expression in mouse hair follicle morphogenesis and cycling.
The hr (hairless) gene encodes a putative transcription factor with restricted expression in the skin and brain. Mutations in the hr locus cause papular atrichia in humans and complete hair loss in mice and other mammals. To further elucidate the role of hr in skin biology, and to identify potential target cells for hr regulation, we studied hr mRNA localization during hair follicle (HF) morphogenesis and cycling in normal C57BL/6J mice. In situ hybridization revealed that hr expression was present in the suprabasal cell layers of the epidermis, whereas the basal and highly differentiated keratinocytes of the granular layer were hr-negative. During the early stages of HF morphogenesis, hr mRNA was detected in the developing hair peg. Later, it became concentrated in the HF infundibulum, in the HF matrix, and in the inner root sheath (IRS), whereas the dermal papilla (DP) and outer root sheath were consistently hr mRNA-negative. During catagen, hr gene expression gradually declined in the regressing IRS, shortly but dramatically increased in the zone of developing club hair, and became up-regulated in the epithelial cells adjacent to the DP. The co-localization of hr mRNA with the site of the morphological defects in mutant skin implicates hr as a key factor in regulating basic cellular processes during catagen, including club hair formation, maintenance of DP-epithelial integrity, IRS disintegration, and keratinocyte apoptosis in the HF matrix. (+info)
In vivo patch-clamp analysis of IPSCs evoked in rat substantia gelatinosa neurons by cutaneous mechanical stimulation.
To know a functional role of inhibitory synaptic responses in transmitting noxious and innoxious information from the periphery to the rat spinal dorsal horn, we examined inhibitory postsynaptic currents (IPSCs) elicited in substantia gelatinosa (SG) neurons by mechanical stimuli applied to the skin using the newly developed in vivo patch-clamp technique. In the majority (80%) of SG neurons examined, a brush stimulus applied to the ipsilateral hind limb produced a barrage of IPSCs that persisted during the stimulus, while a pinch stimulus evoked IPSCs only at its beginning and end. The pinch-evoked IPSCs may have been caused by a touch that occurs at the on/off time of the pinch. The evoked IPSCs were blocked by either a glycine-receptor antagonist, strychnine (4 microM), or a GABA(A)-receptor antagonist, bicuculline (20 microM). All SG neurons examined received inhibitory inputs from a wide area throughout the thigh and lower leg. When IPSCs were examined together with excitatory postsynaptic currents (EPSCs) in the same neurons, a brush evoked a persistent activity of both IPSCs and EPSCs during the stimulus while a pinch evoked such an activity of EPSCs but not IPSCs. It is suggested that innoxious mechanical stimuli activate a GABAergic or glycinergic circuitry in the spinal dorsal horn. This inhibitory transmission may play an important role in the modulation of noxious information in the SG. (+info)