Both interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) are crucially involved in the fibrotic events characterizing interstitial lung diseases (ILDs). Therefore, the aim of this study was to investigate, in primary cultures of normal and fibrotic human lung fibroblasts (HLFs) exposed to either IL-6 or TGF-beta1, the effects on phosphorylation of mitogen-activated protein kinases (MAPK) and cell growth of IL-6 signaling inhibition, performed by the IL-6 receptor superantagonist Sant7. MAPK phosphorylation was detected by Western blotting, HLF viability and proliferation were evaluated using Trypan blue staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. Sant7, at a concentration of 1 μg/ml, was capable of significantly inhibiting HLF proliferation and MAPK phosphorylation induced by cell exposure to IL-6 (100 ng/ml) or TGF-beta1 (10 ng/ml), whose actions were much more prominent in fibrotic cells. These results thereby suggest that, in HLFs derived from patients with ILDs, the proliferative mechanisms activated by TGF-beta1 are at least in part mediated by an increased release of IL-6, leading to phosphorylation-dependent MAPK activation. Such preliminary findings may thus open new therapeutic perspectives for fibrogenic ILDs, based on inhibition of signal transduction pathways stimulated by the IL-6 receptor.
Inhibitory effects of the IL-6 receptor superantagonist SANT7 on MAP kinase phosphorylation and cell proliferation induced by IL-6 and TGF-beta1in human lung fibroblasts
VATRELLA, Alessandro;
2008-01-01
Abstract
Both interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) are crucially involved in the fibrotic events characterizing interstitial lung diseases (ILDs). Therefore, the aim of this study was to investigate, in primary cultures of normal and fibrotic human lung fibroblasts (HLFs) exposed to either IL-6 or TGF-beta1, the effects on phosphorylation of mitogen-activated protein kinases (MAPK) and cell growth of IL-6 signaling inhibition, performed by the IL-6 receptor superantagonist Sant7. MAPK phosphorylation was detected by Western blotting, HLF viability and proliferation were evaluated using Trypan blue staining and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. Sant7, at a concentration of 1 μg/ml, was capable of significantly inhibiting HLF proliferation and MAPK phosphorylation induced by cell exposure to IL-6 (100 ng/ml) or TGF-beta1 (10 ng/ml), whose actions were much more prominent in fibrotic cells. These results thereby suggest that, in HLFs derived from patients with ILDs, the proliferative mechanisms activated by TGF-beta1 are at least in part mediated by an increased release of IL-6, leading to phosphorylation-dependent MAPK activation. Such preliminary findings may thus open new therapeutic perspectives for fibrogenic ILDs, based on inhibition of signal transduction pathways stimulated by the IL-6 receptor.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
