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To cite this article: Jensen JM, Scherer A, Wanke C, Bräutigam M, Bongiovanni S, Letzkus M, Staedtler F, Kehren J, Zuehlsdorf M, Schwarz T, Weichenthal M, Fölster-Holst R, Proksch E. Gene expression is differently affected by pimecrolimus and betamethasone in lesional skin of atopic dermatitis. Allergy 2012; 67: 413-423. Abstract Background: Topical corticosteroids and calcineurin inhibitors are well-known treatments of atopic dermatitis (AD) but differ in their efficacy and side effects. We recently showed that betamethasone valerate (BM) although clinically more efficient impaired skin barrier repair in contrast to pimecrolimus in AD. Objective: This study elucidates the mode of action of topical BM and pimecrolimus cream in AD. Methods: Lesional AD skin samples after topical treatment with either BM or pimecrolimus were subjected to gene expression profile analysis. Results: Betamethasone valerate resulted in a significant reduction in mRNA levels of genes encoding markers of immune cells and inflammation, dendritic cells, T cells, cytokines, chemokines, and serine proteases, whereas pimecrolimus exerted minor effects only. This corroborates the clinical finding that BM reduces inflammation more effectively than pimecrolimus. Genes encoding molecules important for skin barrier function were differently affected. Both BM and pimecrolimus normalized the expression of filaggrin and loricrin. BM, but not pimecrolimus, significantly reduced the expression of rate-limiting enzymes for lipid synthesis and the expression of involucrin and small proline-rich proteins, which covalently bind ceramides. This may explain the lack of restoration of functional stratum corneum layers observed after BM treatment. Conclusion: The gene expression profiles are consistent with our previous findings that corticosteroids may exert a more potent anti-inflammatory effect but may impair the restoration of the skin barrier. Corticosteroids are still the main treatment for severe and acutely exacerbated AD; pimecrolimus may be preferable for long-term treatment and stabilization. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Repeated injection of streptococcal cell wall (SCW) fragments results in chronic arthritis in mice. The objective of this study was to identify genes and pathways that determine disease progression based on gene expression profiling in this model. METHODS: Chronic arthritis was induced in mice by 4 injections of SCW fragments. RNA samples were isolated from synovial tissue obtained at various time points and were analyzed using mouse genome array and quantitative reverse transcription-polymerase chain reaction techniques. The functional role of potential key genes was evaluated in mice with specific gene deletions. RESULTS: Gene expression analyses revealed a shift in molecular signature. In contrast to an up-regulation of the inflammatory response pathway, the pathways involved in oxidative metabolism were significantly down-regulated during the chronic phase of arthritis. Since oxidative metabolism determines the mode of macrophage activation, we investigated phenotype switching in macrophages. Markers of alternatively activated macrophages, such as arginase 1, were at maximal levels during acute inflammation. In contrast, induction of markers of classically activated macrophages (M1), such as interleukin-1beta (IL-1beta) and inducible nitric oxide synthase (iNOS), was relatively low during the acute phase of disease, but highly increased toward the chronic phase. M1 polarization during the chronic phase was accompanied by a Th1 signature, characterized by IL-12p40, IL-12p35, and interferon-gamma. However, the absence of IL-12p40, but not IL-12p35, significantly inhibited the chronic phase of arthritis and was marked by a reduction in IL-17 and iNOS levels, as well as restored expression of oxidative metabolism genes. CONCLUSION: M1 polarization accompanied by a decline in oxidative metabolism determine the chronic phase of arthritis. IL-12p40, most likely acting through the IL-23/IL-17 axis, plays a critical role in this process. [ABSTRACT FROM AUTHOR]