The dissociated steroid receptor ligand from plant origin called compound A (CpdA) inhibits the production of steroid-resistant chemokines induced by TNFα/IFNγ in airway smooth muscle (ASM) cells in both asthma and healthy subjects

Corticosteroids (GC) act by two molecular mechanisms known as transactivation or transrepression. Transrepression mediates the vast majority of the anti-inflammatory actions of corticosteroids, whereas transactivation has been associated with the unwanted side effects of corticosteroids. One unanswered question is whether compounds that can dissociate the transactivation from the beneficial transrepression function of GC could be used to treat severe patients who are refractory to steroid therapy. The purpose of the present study was to study the effect of CpdA, a dissociated steroid receptor ligand, on the production of steroid-resistant chemokines induced by TNFα/IFNγ in ASM cells. We found that TNFα/IFNγ combination stimulates the expression of CXCl10, CCl5 and CX3Cl1 in both asthmatic and healthy airway smooth muscle cells, with a greater production of CXCl10 and CCl5 by asthmatic cells (n=3 subjects). Pretreating cells with fluticasone (100 nM, 2 hr) did not affect cytokine-induced expression of CXCl10 while CX3Cl1 levels were significantly increased by 2.3 fold in the presence of fluticasone. Interestingly, CpdA (5 μM) suppressed cytokine-induced expression of CXCl10 by 50% while CCl5 and CX3Cl1 responses were completely inhibited in both asthmatic and healthy cells. These data show that CpdA can inhibit the expression of steroid-resistant inflammatory genes in airway smooth muscle cells. This study suggests that dissociated steroid receptor ligands could offer a novel therapeutic alternative to treat steroid resistance in severe asthmatics.