Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that strongly activates dendritic cells (DC) and can initiate allergic inflammation. The factors inducing the production of human TSLP are not known. In this study, we show that proinflammatory (TNF-α or IL-1α) and Th2 (IL-4 or IL-13) cytokines synergized to induce the production of TSLP in human skin explants. TSLP production in situ was restricted to epidermal keratinocytes of the suprabasal layer. TSLP production could not be inhibited by factors regulating Th2 inflammation, such as IL-10, TGF-β, or IFN-γ. Cytokine-treated skin culture supernatants induced the maturation of blood CD11c+ DC in a TSLP-dependent manner. Our data provide the first evidence of TSLP induction and subsequent DC activation in human skin. Blocking TSLP-inducing cytokines could represent a novel strategy for the treatment of allergic diseases.

Chroma a*-, AU 5.82 ± 0.5 5.76 ± 0.5 12.05 ± 1.34 a***, b*** 5.64 ± 0.61 Skin pH, AU 5.09±0.16 4.97±0.13 6.11±0.19 a**, b** 5.12±0.15 Capacitance, AU 37.3 ± 1.78 37.36 ± 1.76 19.22 ± 2.10 a***, b*** 36.63 ± 1.76 B. Single 24-h application of 2% SLS Parameter Baseline SLS-treated field Baseline control field + 24 h SLS-treated field + 24 h control field TEWL, g m À2 h À1 6.21 ± 0.18 5.51 ± 0.36 42.16 ± 7.76 a**, b** 5.41 ± 0.30 Chroma a*-, AU 6.76 ± 0.24 6.69 ± 0.31 12.23 ± 1.54 a*, b** 5.93 ± 0.25 Skin pH, AU 4.96±0.35 5.26±0.19 7.15±0.08 a*, b** 4.92±0.12 Capacitance, AU 51.84±2.28 50.49±2.77 32.20±5.31 a**, b* 49.29±2.95 C. Tape stripping Parameter Baseline TS field +100 Strips TS field Control field TEWL, g m À2 h À1 4.83 ± 0.66 61.57 ± 1.92 a***, b*** 4.82 ± 0.65 Chroma a*-, AU 3.66 ± 1.21 10.87 ± 1.84 a**, b** 3.80 ± 0.99 Abbreviations: AU, arbitrary units; SLS, sodium lauryl sulfate; TEWL, transepidermal water loss; TS, tape stripping. All data are presented as mean ± SEM and differences are considered significant when Po0.05. a Values compared with baseline; b values compared with control field; *Po0.05; **Po0.01; ***Po0.001.

Shigella flexneri causes bacillary dysentery in humans by invading epithelial cells of the colon, which is characterized by an acute polymorphonuclear leukocyte (PMNL)-rich inflammation. Our recent studies demonstrated that cadaverine, a polyamine, specifically acts to abrogate transepithelial signaling to PMNL induced by S. flexneri. Here, insight is provided into the cellular mechanisms by which cadaverine attenuates the ability of Shigella species to induce PMNL signaling. It was found that cadaverine retards the lysis of the Shigella species-containing vacuole, suggesting that a blockade is established, in which the pathogen is prevented from adequately interacting with the cytoskeleton. Furthermore, an IcsA mutant of S. flexneri that cannot interact with the cytoskeleton and spreads intercellularly fails to induce transmigration of PMNL. Results indicate that cadaverine-induced compartmentalization of Shigella species to the phagolysosome might be a protective response of the host that directly contributes to the diminished ability of PMNL to transmigrate across model intestinal epithelia.