AN ESSENTIAL ROLE FOR LANGERHANS CELL-DERIVED IL-1-BETA IN THE INITIATION OF PRIMARY IMMUNE-RESPONSES IN SKIN

Langerlians cells (LC) are Ag-presenting cells required for induction of primary immune responses in skin. After activation by Ag, LC expres s increased levels of MHC class II Ag, exhibit increased accessory cel l activity, and migrate to regional lymph nodes where they stimulate T cells. One of the earliest manifestations of LC activation is the acc umulation of increased amounts of IL-1 beta mRNA in LC within 15 min a fter exposure to contact allergens in vivo. To determine if enhanced I L-1beta production by LC could be causally linked to epicutaneous sens itization, we injected IL-1beta intradermally into the ears of BALB/c mice and extracted total epidermal RNA 4 h later. A quantitative rever se transcriptase-polymerase chain reaction technique was used to compa re changes in IL-1alpha, IL-1beta, macrophage inflammatory protein 2, IL-10, TNF-alpha, and I-Aalpha chain mRNA signals caused by intraderma lly-injected IL-1beta to those caused by intradermal IL-1alpha or TNFa lpha, or by topical application of the contact allergen trinitrochloro benzene (3% TNCB). Intradermal injection of 25 ng IL-1beta resulted in 5-to 100-fold enhancement of mRNA signals for IL-1alpha, IL-1beta, MI P-2, IL-10, TNFalpha, and class II I-Aalpha, mimicking the changes cau sed by allergen. In contrast, injection of equivalent amounts of IL-1a lpha or TNFalpha did not significantly alter the epidermal cytokine pa ttern. Simulating the effects of topically applied TNCB, intradermally -injected IL-1beta (but not IL-1alpha or TNFalpha) also caused enhance ment of LC MHC class II expression. In addition, LC derived from IL-1b eta-injected skin were 2 to 3 times more potent accessory cells in an anti-CD3 proliferation assay than LC from IL-1alpha or sham-injected s kin. Finally, injection of hamster anti-mIL-1beta mAb into the skin pr ior to TNCB treatment completely prevented sensitization to this aller gen, although injections of similar amounts of hamster anti-mlL-1alpha mAb or PBS were without effect. Taken together, our data indicate tha t dendritic cell-derived IL-1beta may be a critical molecule required for initiation of primary immune responses in skin.