IL-25 enhances T H 17 cell-mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells.

BACKGROUND: In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce TH 2 cytokine production by various cell types, including TH 2 cells, TH 9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in TH 2-type immune responses. Because both TH 2-type and TH 17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing TH 2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate-induced CHS is poorly understood.

OBJECTIVE: We investigated the contribution of IL-25 to CHS using Il25-/- mice.

METHODS: CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific TH cell differentiation, and detection of IL-1β-producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively.

RESULTS: In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific TH cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell- and non-immune cell-derived IL-25 was important for hapten-specific TH 17 cell-mediated rather than TH 2 cell-mediated inflammation in the elicitation phase of CHS by enhancing TH 17-related, but not TH 2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific TH 17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS.

CONCLUSION: Our results identify a novel IL-25 inflammatory pathway involved in induction of TH 17 cell-mediated, but not TH 2 cell-mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.