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Melanoma progression and resistance to therapy are associated with faulty regulation of signalling molecules including the central transcription factor NF‐κB. Increased expression of the c‐Rel subunit of NF‐κB has been described in progressing melanoma, though mechanistic implications of this upregulation remain unclear. To elucidate the functional role of c‐Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c‐Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c‐Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, chromosomal stability. Our results highlight a novel tumor‐promoting function of c‐Rel in human melanoma cells through governing cell cycle regulation. [ABSTRACT FROM AUTHOR]

T-cells expressing αE( CD103), an integrin induced by TGFβ on T-cells in vitro, accumulate within epithelia in inflammatory disorders, including psoriasis. However, it is unclear, if and how αE( CD103) contributes to skin inflammation. Using two complementary approaches, we have investigated αE( CD103) in psoriasis-like skin inflammation of mice with transgenic epidermal expression of human TGFβ1: αE( CD103) was inhibited by function-blocking antibodies in vivo, and double-mutants with additional αE( CD103)-depletion were generated in two different genetic backgrounds. Epidermal h TGFβ1 expression was associated with prominent expression of αE( CD103) on infiltrating cells. However, neither treatment with αE( CD103)-blocking antibodies nor deficiency of αE( CD103) in double-mutant mice altered the psoriasis-like phenotype. In addition, histopathological and flow cytometric analyses revealed similar pathological skin alterations and lymphocyte subgroups in the different mouse strains. Thus, while αE( CD103) expression is indeed associated with h TGFβ1 in vivo, it has little, if any, influence on the course of the psoriasis-like phenotype in K5.h TGFβ1 transgenic mice. [ABSTRACT FROM AUTHOR]

The xeroderma pigmentosum ( XP) group D protein is involved in nucleotide excision repair ( NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy ( TTD), XP⁄ TTD complex, XP⁄ Cockayne syndrome ( CS) complex or the cerebro-oculo-facio-skeletal syndrome ( COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post- UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/ CS complex phenotypes, respectively. Interestingly, the XP/ CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status. [ABSTRACT FROM AUTHOR]

Comments on receptor-selective antiinflammatory strategies that target leukocyte extravasation. View by the author that the functions of chemokines overlap; Link between extravasation and other cellular functions; Levels of complex interactions that influence the success of therapeutic strategies aimed at leukocyte extravasation.

The author reflects on the different cells responsible in controlling the skin immune system. According to the author, determining the single cell responsible for securing skin homeostasis is one difficult task. The particular relevance of a given cell type under physiological conditions becomes evident only when its function is perturbed or lost.

To use mice with chronic hyperproliferative skin inflammation as psoriasis models, their thorough phenotypic and functional characterization is indispensable. Mice with keratin 5 promoter-controlled overexpression of latent human Transforming Growth Factor (TGF)beta1 within the basal epidermis (K5.TGF beta 1 mice) show a psoriasiform phenotype, but the underlying pathogenic mechanisms are not entirely clear. To elucidate the contribution of T lymphocytes to the pathogenesis in K5.TGF beta 1 mice, we used three complementary approaches: first, peripheral T cells were eradicated via systemic treatment with CD3- or CD4-depleting antibodies. However, this elimination did not alleviate the chronic inflammatory disorder. Second, bone marrow transplantation from transgenic mice into wildtype recipients and vice versa resulted in the expected reconstitution of both adaptive and innate immune system but had little effect on the cutaneous phenotype both in wildtype and transgenic chimeras. Third, based on the hypothesis that the disease course could be modulated by regulatory T cells (Tregs), we expanded Tregs in vivo using a superagonistic anti-CD28 antibody. While this treatment achieved a threefold increase in Foxp3-expressing Tregs, there was little, if any, effect on the chronic skin inflammation. We conclude from our findings that T cells play little, if any, role in the skin lesions of K5.TGF beta 1 mice.