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S100A8/A9 promotes NADPH oxidase in HaCaT keratinocytes and subsequently increases NFκB activation, which plays important roles in the balance between epidermal growth and differentiation. S100A8/A9-positive HaCaT cells present with a significantly reduced rate of cell division and greater expression of two keratinocyte differentiation markers, involucrin and filaggrin, than control cells. S100A8/A9 mutants fail to enhance NFκB activation, TNFα-induced IL-8 gene expression and NFκB p65 phosphorylation, and S100A8/A9-positive cells demonstrate better cell survival in forced suspension culture than mutant cells. S100A8/A9 is induced in epithelial cells in response to stress. Therefore, S100A8/A9-mediated growth arrest could have implications for tissue remodeling and repair., (Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1beta, osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen.

IL-15 is involved in lymphocyte homeostasis. To investigate the role of IL-15 in the skin in vivo, mice were generated that overexpress IL-15 in keratinocytes, resulting in increased IL-15 protein levels in the skin but not elevated IL-15 serum concentrations. Keratin 14 (K14)-IL-15 transgenic (tg) mice showed increased contact hypersensitivity (CHS) responses. Transfer of primed wild-type (wt) and tg T cells into naive wt or tg recipients indicated that skin-derived IL-15 enhanced the induction but not the elicitation phase of CHS. Tg mice could be sensitized even by suboptimal hapten concentrations. Accordingly, Langerhans cells (LC) from tg skin were identified as potent allostimulators, suggesting the involvement of IL-15-stimulated LC in the induction of adaptive immunity. Overexpression of IL-15 also strengthened innate immunity since tg mice infected with human HSV type I developed significantly smaller HSV skin lesions. In addition, tg mice resisted re-infection with HSV more effectively than wt mice did, which was associated with an elevated anti-HSV Ab production. Accordingly, injection of serum from re-infected tg mice protected naive recipients significantly from epicutaneous HSV infection, indicating that anti-HSV Ab produced by tg mice play an important role in resistance in vivo. Together, our results show that overexpression of IL-15 in the epidermis enhances both innate and adaptive cutaneous immunity.

To decipher early promoters of the local microenvironment for Th2-type immunity, we wanted to identify gene patterns that were induced by Leishmania major in the infected skin of susceptible, Th2-prone BALB/c, but not of resistant, Thl-prone C57BL/6 mice. We found a marked up-regulation of the chemokine I-TAC (Cxclll) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. Accordingly, local injection of I-TAC (2x1 |xg) in resistant mice on the first day of infection resulted in a Th2-driven, sustained deterioration of disease and dramatically enhanced parasite levels. On the cellular level, I-TAC decreased IL-12 production by dendritic cells (DCs) in skindraining lymph nodes and by DCs in vitro. Thus, we demonstrate for the first time that epidermis-derived I-TAC triggers a sustained Th2-response that determines the outcome of a complex immunological process. [ABSTRACT FROM AUTHOR]