Melanie K. Kuechle

Interleukin 20: discovery, receptor identification, and role in epidermal function.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

Processing of native caspase-14 occurs at an atypical cleavage site in normal epidermal differentiation.

Caspase-14, a cysteinyl aspartate-specific protease expressed during epidermal differentiation, is detected exclusively in the cytosolic fraction of epidermis as a complex of procaspase-14 together with caspase-14 large and small subunits. On non-denaturing protein gels, native caspase-14 has a relative electrophoretic mobility of approximately 80kDa, which resolves into caspase-14 proform, large and small subunit in SDS-polyacrylamide. Purification of caspase-14 from native skin with subsequent N-terminal sequencing of the small subunit and tryptic digest analysis of the large subunit revealed an atypical processing site between Ile152 and Lys153, which distinguishes it from other caspases described to date that are processed at aspartate residues. Expression of caspase-14 in heterologous systems results in unprocessed procaspase-14 without generation of the large and small subunits that characterize this protein family. However, addition of cellular extracts to purified recombinant human caspase-14 generated immunoreactive peptides indistinguishable from large and small subunits in skin. These data provide evidence for novel processing of caspase-14 suggesting that this enzyme has unique mechanisms of regulation during epidermal differentiation.

Fibroblast and endothelial apoptosis in systemic sclerosis

Purpose of reviewSystemic sclerosis is a disease characterized by vascular and skin changes associated with activation of fibroblasts and increased synthesis of matrix components. These abnormalities lead to fibrosis and impaired function of internal organs such as the lung, kidney, and gastrointestinal tract. Recent evidence suggests that although activation of cells in and around the blood vessels and in the skin occurs in systemic sclerosis, injury to the vascular endothelium and defective apoptosis of skin fibroblasts may also contribute to disease. The purpose of this review is to discuss these findings in the context of the pathophysiology of systemic sclerosis. Recent findingsThis review highlights concepts and recent findings relating to apoptosis of vascular endothelium and skin fibroblasts. Important paradigms of fibroblast cell death in wound healing and keloid formation are discussed. Recent observations describing resistance of systemic sclerosis fibroblasts to Fas-mediated apoptosis and activation of the antiapoptotic protein kinase, Akt, are mentioned as possible contributors to fibroblast selection in this disease. SummaryImproved understanding of how death and survival signals affect vascular endothelial cells and skin and visceral fibroblasts will lead to new approaches to therapy.

Caspase-14, a keratinocyte specific caspase : mRNA splice variants and expression pattern in embryonic and adult mouse

Caspase-14, a keratinocyte specific caspase: mRNA splice variants and expression pattern in embryonic and adult mouse

Inducible expression of filaggrin increases keratinocyte susceptibility to apoptotic cell death.

Filaggrin is an intermediate filament associated protein that aids the packing of keratin filaments during terminal differentiation of keratinocytes. Premature aggregation of keratin filaments is prevented by filaggrin expression as the inactive precursor, profilaggrin, which is localized in keratohyalin granules in vivo. We have previously shown that filaggrin constructs, when transiently transfected into epithelial cells, lead to a collapsed keratin cytoskeletal network and dysmorphic nuclei with features of apoptosis. The apparent transfection rate is low with filaggrin constructs, supporting their disruptive role but hindering further study. To bypass this problem, we generated stable keratinocyte cell lines that express mature human filaggrin using a tetracycline-inducible promoter system. We found that cell lines expressing filaggrin, but not control cell lines, exhibited increased sensitivity to multiple apoptotic stimuli as measured by morphologic and biochemical criteria. None of the cell lines showed an increase in endogenous expression of filaggrin in response to the same stimuli. Filaggrin expression alone was insufficient to induce apoptosis in these keratinocyte cell lines. We conclude that filaggrin, due to its keratin binding ability, primes cells for apoptosis. Because filaggrin is expressed at a level of the epidermis where keratinocytes are in transition between the nucleated granular and the anucleate cornified layers, we hypothesize that filaggrin aids in the terminal differentiation process by facilitating apoptotic machinery. Cell Death and Differentiation (2000) 7, 566–573

Neonatal eosinophilic pustulosis

A pre‐term, 7‐week‐old male infant presented with a recurrent pustular eruption involving his face and scalp with associated peripheral blood eosinophilia. Skin biopsy revealed spongiosis with numerous dermal and epidermal eosinophils without predominant follicular involvement. Immunohistology showed deposition of eosinophil granule major basic protein and eosinophil derived neurotoxin in the dermis and epidermis. He responded to conservative management. We discuss the differential diagnosis of neonatal eosinophilic pustular eruptions and suggest the term ‘neonatal eosinophilic pustulosis’ to best describe our case.