An essential role for langerhans cell-derived IL-1β in the initiation of primary immune responses in skin

Langerhans cells (LC) are Ag-presenting cells required for induction of primary immune responses in skin. After activation by Ag, LC express increased levels of MHC class II Ag, exhibit increased accessory cell activity, and migrate to regional lymph nodes where they stimulate T cells. One of the earliest manifestations of LC activation is the accumulation of increased amounts of IL-1β mRNA in LC within 15 min after exposure to contact allergens in vivo. To determine if enhanced IL-1β production by LC could be causally linked to epicutaneous sensitization, we injected IL-1β intradermally into the ears of BALB/c mice and extracted total epidermal RNA 4 h later. A quantitative reverse transcriptase-polymerase chain reaction technique was used to compare changes in IL-1α, IL-1β, macrophage inflammatory protein 2, IL-10, TNF-α, and l-Aα chain mRNA signals caused by intradermallyinjected IL-1β to those caused by intradermal IL-1α or TNFα, or by topical application of the contact allergen trinitrochlorobenzene (3% TNCB). Intradermal injection of 25 ng IL-1β resulted in 5-to 100-fold enhancement of mRNA signals for IL-1α, IL-1β, MIP-2, IL-10, TNFα, and class II 1-Aα, mimicking the changes caused by allergen. In contrast, injection of equivalent amounts of IL-1α or TNFα did not significantly alter the epidermal cytokine pattern. Simulating the effects of topically applied TNCB, intradermally-injected IL-1β (but not IL-1α or TNFα) also caused enhancement of LC MHC class II expression. In addition, LC derived from IL-1β-injected skin were 2 to 3 times more potent accessory cells in an anti-CD3 proliferation assay than LC from IL-1α or sham-injected skin. Finally, injection of hamster anti-mlL-1β mAb into the skin prior to TNCB treatment completely prevented sensitization to this allergen, although injections of similar amounts of hamster anti-mlL-1α mAb or PBS were without effect. Taken together, our data indicate that dendritic cell-derived IL-1β may be a critical molecule required for initiation of primary immune responses in skin.