Cytokine Responses Induced by Skin Exposure of Mice to Chemical Allergens: Role of Interleukin 12

Abstract

We reported previously that prolonged (13 day) topical exposure to chemical contact and respiratory allergens such as 2,4‐dinitrochlorobenzene (DNCB) and trimellitic anhydride (TMA) results in cytokine phenotypes consistent with the selective activation of type 1 and type 2 cells, respectively. In the current experiments, the role of the type 1 inducing heterodimeric cytokine interleukin (IL)‐12 in the development of these divergent cytokine secretion phenotypes has been examined by using an enzyme‐linked immunosorbant assay and neutralizing antibody specific for the p40 subunit of the dimer. After acute exposure, when a mixed Th0 phenotype is observed following treatment with allergen, both DNCB‐ and TMA‐activated lymph node cells (LNC) secrete similar levels of interferon‐γ (IFN‐γ) and IL‐12 p40, and neutralizing anti‐IL‐12 p40 antibody profoundly inhibits expression of IFN‐γ by both DNCB‐ and TMA‐stimulated LNC. After more prolonged treatment, divergent IFN‐γ and IL‐12 p40 production is recorded, with DNCB treatment inducing much higher levels of both cytokines than did identical exposure to TMA. Macrophage depletion studies have shown that the cellular source of IL‐12 p40 is primarily nonphagocytic cells. Given that DNCB‐ and TMA‐activated LNC are expressing similar levels of IL‐12 p40 and equivalent functional activity of IL‐12 with respect to IFN‐γ production following acute exposure, it seems unlikely that the divergent cytokine profiles observed following chronic exposure to allergen are being driven by differential IL‐12 production. As the response polarizes, a divergent capacity to express p40 IL‐12 is apparent, as is the functional activity of this cytokine, with IFN‐γ secretion by DNCB‐activated T helper 1 (Th1) and T cytotoxic 1 (Tc1) cells inhibited by neutralizing antibody, whereas TMA‐stimulated Tc1 cells are refractory to anti‐IL‐12 p40 antibody. These results show that the phenotype of mature DNCB‐ and TMA‐activated LNC is even more polarized than demonstrated previously, with exposure to TMA, but not to DNCB, resulting in a loss of functional responsiveness to IL‐12 p40, presumably as a result of loss of functional IL‐12 receptor expression.

Keywords :

• Chemical allergen
• Cytokines
• T helper cell
• T cytotoxic cell
• Interleukin 12