Collagenase-3 (MMP-13) enhances remodeling of three-dimensional collagen and promotes survival of human skin fibroblasts

Collagenase-3 (MMP-13) is a matrix metalloproteinase capable of cleaving a multitude of extracellular matrix proteins in addition to fibrillar collagens. Human MMP-13 is expressed by fibroblasts in chronic cutaneous ulcers, but not in normally healing adult skin wounds. However, MMP-13 is produced by fibroblasts in adult gingival and in fetal skin wounds characterized by rapid collagen remodeling and scarless healing. Here, we have examined the role of human MMP-13 in remodeling of three-dimensional (3D) collagenous matrix by primary adult human skin fibroblasts. The high level of human MMP-13 expression by fibroblasts achieved by adenoviral gene delivery resulted in potent enhancement of remodeling and contraction of 3D collagen. Fibroblasts expressing MMP-13 in 3D collagen possessed altered filamentous actin morphology with patch-like actin distribution in cell extensions. The expression of MMP-13 promotes survival and proliferation of fibroblasts in floating collagen gel, and results in activation of Akt and extracellular signal-regulated kinase-1/2 by these cells. The results provide evidence for a novel role for human MMP-13 in regulating dermal fibroblast survival, proliferation, and interaction in 3D collagen, which may be an important survival mechanism for fibroblasts in chronic skin ulcers and contribute to scarless healing of adult gingival and fetal skin wounds.     

Hyaluronan and CD44 in psoriatic skin. Intense staining for hyaluronan on dermal capillary loops and reduced expression of CD44 and hyaluronan in keratinocyte-leukocyte interfaces

The distributions of hyaluronan (HA) and its presumptive receptor, CD44, were studied in skin samples from 13 psoriasis vulgaris patients, using an HA-specific probe (HABC), and monoclonal antibodies, respectively. The general distribution of HA and CD44 in psoriatic lesional epidermis resembled that in normal epidermis. However, areas of epidermis invaded by leukocytes showed a local depletion of HA and CD44, particularly at the contact areas of keratinocytes to lymphocytes and neutrophils. Removal by cellular uptake or extracellular degradation of CD44 and HA may be required for tight adherence between a keratinocyte and a leukocyte. On the dermal side, the tips of the prolonged dermal papillae in psoriatic lesions were intensively stained with HABC. The dilated capillaries and the space below the tip basal lamina, in particular, were heavily covered with HA. Occasionally, a similar intense staining was seen around an enlarged capillary in uninvolved psoriatic skin. CD44-positive leukocytes were found around the affected capillaries. The accumulation of HA in the dermal papillae may support the growth of psoriatic lesions, since HA stimulates the growth of capillaries as well as attracting inflammatory cells.     

Epitopes for CD1a, CD1b, and CD1c antigens are differentially mapped on Langerhans cells, dermal dendritic cells, keratinocytes, and basement membrane zone in human skin.

BACKGROUND: CD1 antigens are classified serologically into at least three groups, CD1a, CD1b, and CD1c, and many kinds of monoclonal antibodies are available for each subgroup of CD1 antigens. CD1a, CD1b, and CD1c antigens have been shown to be selectively and differentially expressed on epidermal Langerhans cells and dermal dendritic cells in normal human skin. OBJECTIVE: The objective was to further delineate the localization of epitopes of CD1 antigens in human skin. METHODS: We examined the immunoreactivity of 14 different CD1 antibodies (seven CD1a, five CD1b, and two CD1c antibodies) with the immunoperoxidase technique. We also studied the reactivity of NU-T2 (CD1b) antibody by immunogold electron microscopy. RESULTS: The epitopes for CD1a, CD1b, and CD1c antigens were differentially mapped on epidermal Langerhans cells, dermal dendritic cells, keratinocytes, the luminal portion of eccrine gland ducts, and the basement membrane zone in human skin. CONCLUSION: These CD1 antibodies may be useful to analyze the phenotypic alteration of immune and nonimmune cells in various skin diseases.     

Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity

There is indirect evidence that both skin and hair melanocytes are regulated by the activity of adjacent cells. In hair, the specialized fibroblasts (dermal papilla cells) appear to play a role in the regulation of hair growth. Hair pigmentation may relate to hair growth. In skin, melanocytes are located adjacent to the basement membrane zone. As far as we are aware, direct interactions of fibroblasts with melanocytes have not previously been investigated. Accordingly, the objective of this study was to develop co-culture conditions in which to investigate whether dermal fibroblasts from skin or hair could influence melanocyte differentiation. The influence of fibroblast-conditioned media, co-culture with fibroblasts, and fibroblast-derived extracellular matrix (ECM) on normal human skin melanocyte tyrosinase activity was examined. Fibroblasts from both skin and hair were capable of altering melanocyte morphology and significantly increasing tyrosinase activity when melanocytes were cultured in the absence, but not the presence, of the major proliferative drives. Although stimulation of tyrosinase activity was detectable with conditioned medium and co-culture with fibroblasts, the most striking result was obtained with the fibroblast-produced ECM which, on average, produced a four-fold increase in tyrosinase activity within 6 days. Thus, the study describes co-culture conditions in which the stimulatory effect of the fibroblast on melanocyte differentiation can be examined.     

Thrombomodulin expression on dermal cells in normal and psoriatic skin

Abstract The various subsets of dermal cells with a dendritic appearance can be identified by phenotypic differences in cell markers. We report on the morphology and tissue distribution of dermal cells detected with a monoclonal antibody against thrombomodulin in histological sections of normal arm and scalp skin and psoriatic skin. Double staining with antibodies to factor XIIIa, CD34 and CD68 was also employed in scalp biopsies to elucidate the relationship between thrombomodulin⁺ dermal cells and dermal dendrocytes and macrophages described by others. Thrombomodulin⁺ dermal cells in normal arm skin had little cytoplasm with fine branched dendrites and tended to be localized just beneath the epidermis. In scalp skin these cells had longer, more numerous dendrites and were distributed in the papillae and perivascular adventitial dermis primarily in the upper and central reticular dermis. In psoriatic skin, thrombomodulin⁺ dermal cells had an increased cytoplasmic volume with stout, less branched dendrites and appeared in the papillae and among inflammatory cells. Dermal cells detectable by thrombomodulin expression were factor XIIIa^–, CD34^– and CD68^–, and seemed to represent a distinct subset of dermal cells which may function in tissue repair. However, thrombomodulin⁺ dermal cells and factor XIIIa⁺ dendrocytes were frequently seen close together and could act cooperatively to regulate extravascular thrombin homeostasis in both normal and pathological dermal environments. Received: 26 May 1997     

Cytokines and glucocorticoids differentially regulate APN/CD13 and DPPIV/CD26 enzyme activities in cultured human dermal fibroblasts

Cultured human dermal fibroblasts coexpress two cell surface ectopeptidases, aminopeptidase N (APN/CD13) and dipeptidyl peptidase IV (DPPIV/CD26). These enzymes catalyze the removal of a single amino acid or a dipeptide from the N-termini of oligopeptides, respectively. They are also localized in a differential pattern in normal, non-sun-exposed, adult skin, a finding that supports the supposition that these enzymes might have different functions in the skin, but relatively little is known about their functions in the skin. A better understanding of how the activities of these enzymes are regulated should increase our understanding of their functions in the skin. APN/CD13 was routinely expressed at higher levels on cultured fibroblasts than was DPPIV/CD26. Treatment of cultured fibroblasts with specific factors differentially modulated the activities of these enzymes. APN/CD13 was significantly upregulated by treatment with interleukin-4 (IL-4), interferon (IFN), and the glucocorticoids dexamethasone and hydrocortisone. In contrast, the regulation of DPPIV/CD26 activity was found to be different and more complex. This enzyme was consistently upregulated by IL-1 and IL-1, but consistently downregulated by glucocorticoids, tumor necrosis factor (TNF) and transforming growth factor ₁ (TGF₁). Thus, although these two enzymes are expressed on the same populations of cultured cells, their activities are differentially regulated. This finding, along with their differential distribution in normal skin, suggests that APN/CD13 and DPPIV/CD26 have different functions in the skin.     

Inducible lineage-specific deletion of TbetaRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing

Previous attempts to delete type II TGFbeta receptor (TbetaRII) in fibroblasts have precluded examination of adult mice due to early mortality. We have selectively deleted TbetaRII postnatally in differentiated connective tissue fibroblasts using an inducible Cre-Lox strategy. Tamoxifen-dependent Cre recombinase linked to a fibroblast-specific regulatory sequence from the proalpha2(I)collagen gene permitted deletion of floxed TbetaRII alleles. After postnatal deletion of TbetaRII in fibroblasts, healing of excisional skin wounds in adults showed markedly attenuated dermal scar formation, defective wound contraction and enhanced epidermal proliferation. These findings support a pivotal role for transforming growth factor beta (TGFbeta) signalling in fibroblasts in regulating normal skin wound healing. Explanted dermal fibroblasts from TbetaRII-null-fib mice showed impaired migration and did not generate normal contractile biomechanical forces in fixed collagen gels nor develop alpha-smooth muscle antigen-rich stress fibers in response to TGFbeta1. Surprisingly, some TGFbeta-regulated proteins, including connective tissue growth factor (CTGF), were basally upregulated in TbetaRII-null fibroblasts and this was dependent on extracellular signal-regulated kinase 1/2 activity in these cells. This suggests that other intracellular pathways regulating CTGF expression may partially compensate for disruption of TGFbeta signalling in fibroblasts. Together, our data confirm that expression of TbetaRII in differentiated dermal fibroblasts is essential for normal wound healing and demonstrate a critical role in the development and function of myofibroblasts.     

Prominent CD56 expression by damaged and regenerating muscle fibers in the skin

Background: Antibodies to CD56 label natural killer cells as well as tissues with neural and neuroendocrine differentiation. Despite its apparently limited distribution, other conditions may unexpectedly show strong CD56 expression. Methods: We report three cases to document another setting with strong expression of CD56 in the skin: damaged and/or regenerating muscle fibers. One case of cutaneous lupus erythematosus, one case of lymphomatoid granulomatosis, and one case of a dermal scar adjacent to cutaneous muscle fibers were evaluated with a panel of antibodies, including CD56. Results: All cases showed histopathologic evidence of muscle fiber damage in the setting of lymphocytic infiltration or trauma. All cases showed prominent expression of CD56 by damaged and/or regenerating muscle fibers. The degree of CD56 expression was directly proportional to the proximity to the injury site and inversely proportional to fiber diameter. Conclusions: Even though CD56 is a useful marker for certain cytotoxic lymphomas and neural/neuroendocrine neoplasms, its expression is not limited to these conditions. Our cases highlight another unexpected example of strong CD56 expression in the skin: damaged and/or regenerating muscle fibers. The growing list of CD56‐positive conditions suggests that this marker may not be as specific as initially assumed. Mckay K, McNiff J, Subtil A. Prominent CD56 expression by damaged and regenerating muscle fibers in the skin.     

Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents

Background

During skin wounding and healing, skin homeostasis is interrupted. How the altered epithelial-mesenchymal interactions influence scar formation and epidermogenesis should be investigated using three-dimensional models that are similar to in vivo structures.

Objective

In this study, we assessed the effects of epithelial-mesenchymal interactions on myofibroblast differentiation and how myofibroblasts influence epidermogenesis using a human living skin equivalent (LSE) model.

Methods

We constructed a fibroblast-populated type I collagen gel upon which LSEs were formed by seeding with normal human keratinocytes. Samples of the collagen gel and LSEs were collected at different time points. Myofibroblast differentiation, epidermal differentiation, and proliferation status were investigated immunohistochemically. Several measures were taken to suppress α-smooth muscle actin (α-SMA) expression to determine the effects of myofibroblasts on epidermogenesis, including the addition of basic fibroblast growth factor or a transformation growth factor-β (TGF-β) kinase inhibitor to the culture medium and the inclusion of an amniotic membrane (AM) in the dermal matrix.

Results

The myofibroblast/fibroblast ratio in the fibroblast-populated collagen gel kept rising during culture. In the LSEs, most fibroblasts were α-SMA-negative, except for those along the dermal-epidermal junction. The suppression of α-SMA expression enhanced epidermal differentiation and decreased TGF-β1 expression in the epidermis. The inhibition of TGF-β kinase completely suppressed α-SMA expression in the dermal matrix.

Conclusions

Epidermogenesis suppressed α-SMA expression in the fibroblast-rich dermal matrix, except near the dermal-epidermal junction. The α-SMA-positive cells at the dermal-epidermal junction contributed to the hyperproliferative phenotype of the epidermis. In contrast, the hyperproliferative epidermis expressed more TGF-β1, which is responsible for myofibroblast differentiation.     

Expression of Monocyte/Macrophage Markers (CD13, CD14, CD68) on Human Keratinocytes in Healthy and Diseased Skin

The results of several investigations prove that, in special circumstances, human keratinocytes (HKs) synthesize and express cell surface moieties characteristic of effector and/or accessory cells of the immune system, such as CD16, CD36, HLA-DR, and intercellular adhesion molecule-1 (CD54), which are all detectable on the surfaces of macrophages. In the present study, skin biopsies from healthy volunteers, from positive tuberculin skin tests, and from patients with acute urticaria (AU), lichen planus (LP), psoriasis vulgaris (PV), mycosis fungoides (MF), and purpura pigmentosa chronica (PPC) were investigated by means of a multistep immunoperoxidase method to examine the reactivity of the HKs with a panel of monoclonal antibodies (MABs) characteristic of monocyte/macrophage cell lines. In biopsies obtained from positive tuberculin tests and from clinically involved skin of patients with LP, PV, MF, or PPC, a multifocal, positive peroxidase reaction was observed on the membranes of HKs of the basal and suprabasal cell layers when the MABs OKM13 (CD13), OKM14 (CD14), and Dako-Macrophage (CD68) were used. In contrast, specific staining of the HKs was not observed with the same antibodies in the biopsies of healthy volunteers or of patients with AU or in the uninvolved skin specimens obtained from the other patients. The HKs of PV, LP, MF, PPC, and AU patients and those of the healthy subjects all failed to give positive reactions when MABs against CD11b, CD15, or CD33 were used. The published data supplement the known surface characteristics of HKs, reflecting their stage of activation and differentiation.     

Oxidative defense in cultured human skin fibroblasts and keratinocytes from sun-exposed and non-exposed skin

Skin fibroblasts and keratinocytes cultivated from chronically light-exposed skin sites have higher levels of the protective protein ferritin than cells derived from unexposed areas of the body, suggesting an adaptive response of cells exposed to chronic external insults. In the same line, ferritin levels were always found to be 2-to 7-fold higher in epidermal keratinocytes than in the underlying dermal fibroblasts of the same person thus providing the keratinocyte with continuous protection by the higher cellular ferritin content. The activation of ferritin by oxidative stress including UVA radiation could represent an important cellular defense mechanism that operates in human skin. Following low fluences of UVA radiation (2–4×10⁵ J/m²), ferritin levels increased by 20–30% in normal adult skin fibroblasts and showed a subsequent decrease at higher UVA fluences. In contrast, skin keratinocytes were not perturbed by UVA radiation exposure except for very high fluences (1.25× 10⁶ J/m²) where slight decreases in cellular ferritin were noted in 7 of the 12 cell lines. Fibroblasts derived from light-exposed skin sites that possessed higher levels of cellular ferritin were highly protected against UVA-induced membrane damage as measured by lactate dehydrogenase release compared with fibroblasts from nonexposed body sites with lower levels of ferritin. It is clear from our results that ferritin plays an important role in protection at the cellular level in human skin cells, but the role of this putative protective protein in vivo remains to be defined.     

The receptor for advanced glycation end products is highly expressed in the skin and upregulated by advanced glycation end products and tumor necrosis factor-alpha

Advanced glycation end products (AGEs) form non-enzymatically from reactions of proteins with reducing sugars. In the skin, AGEs were reported to accumulate in dermal elastin and collagens and to interact nonspecifically with the cell membrane of dermal fibroblasts. Therefore, AGEs may influence the process of skin aging. We investigated the presence of the AGE receptor RAGE in skin and the influence of AGEs on receptor expression and the formation of extracellular matrix (ECM). Sections of sun-protected and sun-exposed skin were analyzed with monoclonal antibodies against (RAGE), heat-shock protein 47, factor XIIIa, CD31, and CD45. RAGE was mainly expressed in fibroblasts, dendrocytes, and keratinocytes and to a minor extent in endothelial and mononuclear cells. Human foreskin fibroblasts (HFFs) highly expressed RAGE on the protein and mRNA level when analyzed by quantitative Western blotting and real-time PCR. Incubation of HFFs with the specific RAGE ligand Nepsilon-(carboxymethyl)lysine-modified BSA (CML-BSA) and tumor necrosis factor-alpha resulted in significant upregulation of RAGE expression. CML-BSA induced a mildly profibrogenic pattern, increasing connective tissue growth factor, transforming growth factor-beta (TGF-beta) 1, and procollagen-alpha1(I) mRNA, whereas expression of matrix metalloproteinase (MMP)-1, -2, -3, and -12 was unaffected. We conclude that in HFFs, AGE-RAGE interactions may influence the process of skin aging through mild stimulation of ECM gene expression.     

Molecular control of epithelial-mesenchymal interactions during hair follicle cycling

Epithelial-mesenchymal interactions play pivotal roles in the morphogenesis of many organs and various types of appendages. During hair follicle development, extensive interactions between two embryologically different hair follicle compartments (epidermal keratinocytes and dermal papilla fibroblasts) lead to the formation of the hair shaft-producing mini-organ that shows cyclic activity during postnatal life with periods of active growth, involution and resting. During the hair cycle, the epithelium and the mesenchyme are regulated by a distinct set of molecular signals that are unique for every distinct phase of the hair cycle. In telogen hair follicles, epithelial-mesenchymal interactions are characterized by a predominance of inhibitory signals that retain the hair follicle in a quiescent state. During anagen, a large variety of growth stimulatory pathways are activated in the epithelium and in the mesenchyme, the coordination of which are essential for proper hair fiber formation. During catagen, the termination of anagen-specific signaling interactions between the epithelium and the mesenchyme leads to apoptosis in the hair follicle epithelium, while activation of selected signaling pathways promotes the transition of the dermal papilla into a quiescent state. The signaling exchange between the follicular epithelium and the mesenchyme is modulated by proteoglycans, such as versican, which may significantly enhance or reduce the biological activities of secreted growth stimulators. However, additional research will be required to bridge the gap between our current understanding of mechanisms underlying epithelial-mesenchymal interactions in hair follicles and the potential clinical application of growth modulators involved in those interactions. Further progress in this area of research will hopefully lead to the development of new drugs for the treatment of hair growth disorders.     

Melanocortin receptors in fibroblastic cell types of the skin –in vitro and in vivo expression and functional relevance

In contrast to the well-established role of melanocortins on melanocyte function, the expression and relevance of melanocortin receptors (MC-Rs) in skin fibroblasts is incompletely understood. We recently showed that human dermal fibroblasts derived from foreskin express functional MC-1Rs which mediate an inhibitory action of α-melanocyte-stimulating hormone (α-MSH) on collagen metabolism (Böhm et al., J Biol Chem 2004, in press). Here, we show by RT-PCR, immunofluorescence, immunohistochemistry and immune electron microscopy that MC-1R expression is conserved in vitro and in vivo in additional human fibroblastic cell types of the skin including adult dermal fibroblasts, fibrosarcoma cells, connective tissue sheath fibroblasts and dermal papilla cells of the hair follicle. In vitro expression of MC-1R declines as a matter of cellular senescence in dermal fibroblasts. Interestingly, α-MSH inhibits the inductive effect of interferon-γ, an important proinflammatory mediator in inflammatory and fibrotic skin diseases, on expression of adhesion molecules such as intercellular adhesion molecule-1 in human dermal fibroblasts. These data point towards an additional biological role of α-MSH as a modulator of inflammatory reactions in the connective tissue compartment of the skin.     

Parathyroid hormone-related peptide modulates signal pathways in skin and hair follicle cells

Parathyroid hormone-related protein (PTHrP) is secreted by skin epithelial cells and is thought to play an important role in the development and function of the hair follicle. It was hypothesized that PTHrP binds to receptors in dermal papilla cells and modulates intracellular signaling systems in these cells. We tested the effects of PTHrP on protein synthesis, protein kinase A (PKA) and protein kinase C (PKC) activities as well as tyrosine phosphorylation in rat vibrissa dermal papilla and capsular fibroblast cells. Cells were cultured in the presence or absence of the N-terminal peptide PTHrP1-34 for 48 h and detergent extracts prepared. Proteins were separated by electrophoresis. Phosphotyrosine and the PTH/PTHrP receptor immunoreactivity was identified by Western blot analysis. PKC and PKA activities in the cells were measured using colorimetric enzyme assays. Extracts of both dermal papilla cells and capsular fibroblasts displayed immunoreactivity to the PTH/PTHrP receptor. Electrophoresis showed that PTHrP treatment reduced the density of a 50-kDa protein in dermal papilla cells but not in capsular fibroblasts. Media conditioned by the cells showed similar changes, indicating that the PTHrP-modulated 50-kDa protein was secreted. Furthermore, 2-D gel electrophoresis indicated that the protein had a number of phosphorylation sites. Western analysis with antiphosphotyrosine antibodies confirmed a significant decrease in the intensity of a phosphorylated 50-kDa protein in papilla cells and papilla cell-conditioned medium. PKC and PKA activities of papilla cells were unaffected by PTHrP. However, activities of PKC were increased and PKA reduced in capsular fibroblasts following peptide treatment. These cell-specific effects showed that endogenous PTHrP may activate different intracellular pathways in mesenchymal cells of skin and elicit changes in levels of locally secreted proteins that specifically modulate normal follicular function.     

Perivascular localization of dermal stem cells in human scalp

In mammalian skin, the existence of stem cells in the dermis is still poorly understood. Previous studies have indicated that mesenchymal stem cells (MSCs) are situated as pericytes in various mammalian tissues. We speculated that the human adult dermis also contains MSC-like cells positive for CD34 at perivascular sites similar to adipose tissue. At first, stromal cells from adult scalp skin tissues showed colony-forming ability and differentiated into mesenchymal lineages (osteogenic, chondrogenic and adipogenic). Three-dimensional analysis of scalp skin with a confocal microscope clearly demonstrated that perivascular cells were positive for not only NG2, but also CD34, immunoreactivity. Perivascular CD34-positive cells were abundant around follicular portions. Furthermore, CD34-positive cell fractions collected with magnetic cell sorting were capable of differentiating into mesenchymal lineages. This study suggests that dermal perivascular sites act as a niche of MSCs in human scalp skin, which are easily accessible and useful in regenerative medicine.     

Selective upregulation of fibroblast Fas ligand expression, and prolongation of Fas/Fas ligand-mediated skin allograft survival, by retinoic acid: the skin as a retinoide-inducible immune privilege site

Fas/Fas ligand-mediated lymphocyte apoptosis has been implicated in the suppression of immune responses and may cause immune privilege. Human corneas exhibit immune privilege and can be transplanted across allogeneic barriers without immunosuppressive therapy, perhaps, because corneal keratinocytes express Fas ligand. To characterize Fas and Fas ligand expression in skin, we examined expression by murine keratinocytes, dermal fibroblasts, melanocytes, and human umbilical endothelial cells. We also studied the regulation of Fas and Fas ligand in skin cells by retinoic acid, vitamin D3, and dexamethasone as well as various cytokines. Among the molecules and cells tested, retinoic acid selectively upregulated the expression of Fas ligand molecule by fibroblasts. Retinoic acid-induced Fas ligand+ fibroblasts killed Fas+ target cells, and this killing was blocked by anti-Fas ligand antibody. The function of Fas ligand on dermal fibroblasts in vivo was tested in a cutaneous allograft system. Histoincompatible BALB/C mouse (H-2d) donor skin was grafted on to allogeneic C57BL/6 mice (H-2b). Daily local injection of retinoic acid blocked inflammation and extended graft survival for more than 10 d. Injection of retinoic acid into Fas ligand mutated gld/gld donor skin did not prevent leukocyte infiltration into the allograft or prolong graft survival. These experiments indicate that, in skin, retinoic acid selectively increases Fas ligand expression by fibroblasts and that retinoic acid has potent Fas/Fas ligand-dependent immunosuppressive activity.     

Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling

IL-13 has been implicated in the pathogenesis of allergic diseases, including atopic dermatitis (AD). However, a direct role of IL-13 in AD has not been established. We aimed to develop an inducible transgenic model in which IL-13 can be expressed in the skin and to define the resulting dermal phenotype and mechanisms involved. The keratin 5 promoter was used with a tetracycline-inducible system to target IL-13 to the skin. The clinical manifestations, dermal histology, cytokine gene regulation, and systemic immune responses in the transgenic mice were assessed. IL-13 was produced exclusively in the skin and caused a chronic inflammatory phenotype characterized by xerosis and pruritic eczematous lesions; dermal infiltration of CD4+ T cells, mast cells, eosinophils, macrophages, and Langerhans cells; upregulation of chemokine and cytokine genes, including thymic stromal lymphopoietin; and skin remodeling with fibrosis and increased vasculature. The dermal phenotype was accompanied by elevated serum total IgE and IgG1 and increased production of IL-4 and IL-13 by CD4+ cells from lymphoid tissues and peripheral blood mononuclear cells. IL-13 is a potent stimulator of dermal inflammation and remodeling and this transgenic model of AD is a good tool for investigating the underlying mechanisms in the pathogenesis of AD.