Attenuating Effects of Nortrachelogenin on IL-4 and IL-13 Induced Alternative Macrophage Activation and on Bleomycin-Induced Dermal Fibrosis

Excessive alternative macrophage activation contributes to fibrosis. We studied the effects of nortrachelogenin, the major lignan component of Pinus sylvestris knot extract, on alternative (M2) macrophage activation. J774 murine and THP-1 human macrophages were cultured with IL-4+IL-13 to induce alternative activation, together with the extract and its components. Effects of nortrachelogenin were also studied in bleomycin-induced murine dermal fibrosis model. Knot extract significantly decreased the expression of alternative activation markers-arginase 1 in murine macrophages (97.4 +/- 1.3% inhibition at 30 mu g/mL) and CCL13 and PDGF in human macrophages-as did nortrachelogenin (94.9 +/- 2.4% inhibition of arginase 1 at 10 mu M). Nortrachelogenin also decreased PPAR gamma expression but had no effect on STAT6 phosphorylation. In vivo, nortrachelogenin reduced bleomycin-induced increase in skin thickness as well as the expression of collagens COL1A1, COL1A2, and COL3A1 (all by >50%). In conclusion, nortrachelogenin suppressed IL-4+IL-13-induced alternative macrophage activation and ameliorated bleomycin-induced fibrosis, indicating therapeutic potential in fibrosing conditions.