Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound.

VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)-6, CD86, and human leukocyte antigen (HLA)-DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.

A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation.

RATIONALE AND OBJECTIVE: During allergic lung inflammation dendritic cells (DCs) direct the generation and function of effector T-helper type 2 cells. T-helper type 2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of proinflammatory cells but also induce IgE production by B cells. Thus, inhibitors of DC function should have therapeutic benefits in patients with allergies. METHODS AND MEASUREMENTS: VAF347, a novel low molecular weight immunomodulator, is described and acts as an antiinflammatory compound by a dual mode of action. RESULTS: VAF347 inhibited the function of human monocyte-derived DCs to induce T-cell proliferation and cytokine production. Mechanistically, this effect may be due to reduced expression of CD86, HLA-DR, and interleukin 6 by DCs. In addition, the compound inhibited IgE synthesis in an isotype-specific fashion by human B lymphocytes. In a mouse model of antigen-induced eosinophilic inflammation, VAF347 blocked lung eosinophilia, mucus hyperplasia, and serum IgE levels, representing the hallmarks of allergic lung inflammation. The biological effects in vivo are most likely mediated by the immunoregulatory role of VAF347 on DCs because allergic lung inflammation was also inhibited in B-cell-deficient mice. CONCLUSION: VAF347 represents a novel type of immunomodulator by affecting two major pathways in allergic airway pathogenesis: dendritic cell-mediated T-helper-cell activation and induction of IgE production by human B lymphocytes.