transforming-growth-factor-alpha and Dermatitis--Atopic

Topics: Animals; Cell Communication; Cells, Cultured; Dermatitis, Atopic; Disease Models, Animal; Humans; Keratinocytes; Mice; Plasminogen Activator Inhibitor 1; Pruritus; Receptor, PAR-2; Skin; Transforming Growth Factor alpha; TRPV Cation Channels; Up-Regulation

Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.. To analyze blood inflammatory proteins of early pediatric AD.. Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD.. In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11).. Different baseline expression levels in healthy pediatric vs adult samples.. Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.

Topics: Age Factors; Biomarkers; Case-Control Studies; Chemokines; Child, Preschool; Chronic Disease; Dermatitis, Atopic; E-Selectin; Elafin; Fatty Acid-Binding Proteins; Female; Fibroblast Growth Factors; Humans; Infant; Inflammation; Interleukin-2 Receptor alpha Subunit; Male; Matrix Metalloproteinases; Peroxidase; Proteome; Receptors, Interleukin; RNA, Messenger; Severity of Illness Index; Transforming Growth Factor alpha

Atopic dermatitis (AD) is an inflammatory skin disease characterized by both acute and chronic eczema. Various markers are used to clinically evaluate the severity of AD. In order to identify a marker of local severity of AD, we measured IL-8, IL-18, vascular endothelial growth factor (VEGF), and transforming growth factor-α (TGF-α) levels in the stratum corneum (scIL-8, scIL-18, scVEGF and scTGF-α) and evaluated the correlation between the levels of these cytokines and the clinical severity scores of localized skin lesions.. Stratum corneum samples were collected from the skin lesions of 50 patients with AD using the tape-stripping technique, and the scIL-8, scIL-18, scVEGF and scTGF-α levels were evaluated using the ELISA method. The trans-epidermal water loss and skin water content of the lesions were also measured prior to tape stripping.. The levels of scIL-8, scIL-18, scVEGF and scTGF-α were significantly higher in patients with AD than in healthy controls. Additionally, the levels of scIL-8, scIL-18 and scVEGF significantly correlated with the severity of AD.. Among these cytokines, scIL-8 showed the highest correlation with the severity scores of lesions in AD as well as other parameters. Our results also suggest that measuring cytokines in the stratum corneum by using ELISA combined with tape stripping is a convenient method to evaluate the severity of skin lesions in AD.

Topics: Adolescent; Adult; Biomarkers; Child; Dermatitis, Atopic; Epidermis; Female; Humans; Interleukin-18; Interleukin-8; Male; Middle Aged; Severity of Illness Index; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor A; Young Adult

ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17(ΔKC)) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17(ΔKC) skin, and topical treatment of A17(ΔKC) mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (Egfr(ΔKC)) closely resembled A17(ΔKC) mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17-EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects.

Topics: ADAM Proteins; ADAM17 Protein; Administration, Topical; Animals; Animals, Newborn; Cell Differentiation; Dermatitis, Atopic; Epidermal Cells; Epidermis; ErbB Receptors; Gene Expression Regulation, Developmental; Interleukin-1; Keratinocytes; Macrophages; Mice; Mice, Mutant Strains; Skin; Transforming Growth Factor alpha; Transglutaminases

Recent advances in the knowledge of the EGFR pathway have revealed its contribution to distinct immune/inflammatory functions of the epidermis. The purpose of our study was to evaluate the role of EGFR in the regulation of keratinocyte GM-CSF expression. In cultured human keratinocytes, proinflammatory cytokines synergized with TGF-alpha to induce GM-CSF expression. Accordingly, high epidermal levels of EGFR activation are associated with enhanced expression of GM-CSF in lesional skin of patients with psoriasis or allergic contact dermatitis. In cultured keratinocytes, pharmacological inhibition of EGFR activity reduced GM-CSF promoter transactivation, whereas genetic inhibition of AP-1 reduced expression of GM-CSF. Furthermore, EGFR activation enhanced TNF-alpha-induced c-Jun phosphorylation and DNA binding, whereas c-Jun silencing reduced GM-CSF expression. Using two different mouse models, we showed that the lack of a functional EGFR pathway was associated with reduced cytokine-induced phosphorylation of ERK1/2, JNK1/2, c-Jun and reduced keratinocyte-derived GM-CSF expression both in vitro and in vivo. Finally, the analysis of GM-CSF expression in the skin of cancer patients treated with anti EGFR drugs showed an association between ERK activity, c-Jun phosphorylation, and epidermal GM-CSF expression. These data demonstrate that the EGFR pathway is critical for the upregulation of keratinocyte GM-CSF expression under conditions of cytokine stimulation.

Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cells, Cultured; Cetuximab; Dermatitis, Atopic; Drug Eruptions; ErbB Receptors; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; In Vitro Techniques; Interferon-gamma; JNK Mitogen-Activated Protein Kinases; Keratinocytes; Male; MAP Kinase Signaling System; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Middle Aged; Phosphorylation; Psoriasis; Transcription, Genetic; Transforming Growth Factor alpha