Effect of different interferonα2 preparations on IP10 and ET-1 release from human lung cells

• Published in: PloS one 2012-10, Vol.7 (10), p.e46779-e46779
• Main Authors: Badiger, Rekha, Mitchell, Jane A, Gashaw, Hime, Galloway-Phillipps, Neil A, Foser, Stefan, Tatsch, Fernando, Singer, Thomas, Hansel, Trevor T, Manigold, Tobias
• Format: Article
• Language: English
• Subjects: Bioindicators; Biomarkers; Cell Line; Chronic infection; Conditioning; CXCL10 protein; Cytokines; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelin 1; Endothelin-1 - metabolism; Enzyme-linked immunosorbent assay; Genes; Heart; Hepatitis; Hepatitis C; Humans; Hydrocortisone; Hypertension; Inflammation; Interferon; Interferon-alpha - pharmacology; Lung - cytology; Lung diseases; Medicine; Microvasculature; Muscles; Pharmacology; Pneumonitis; Polyethylene glycol; Proteins; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Receptors, Cytokine - metabolism; Recombinant Proteins - pharmacology; Smooth muscle; Studies; Toxicity; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046779

Alfa-interferons (IFNα2a, IFNα2b, 40KDa-PEGIFNα2a and 12KDa-PEGIFNα2b) are effective treatments for chronic hepatitis C infection. However, their usage has been associated with a variety of adverse events, including interstitial pneumonitis and pulmonary arterial hypertension. Although rare, these adverse events can be severe and potentially life-threatening, emphasizing the need for simple biomarkers of IFN-induced lung toxicity. Human lung microvascular endothelial cells (HLMVEC), human pulmonary artery smooth muscle (HPASM) cells and A549 cells were grown under standard conditions and plated into 96- or 6-well plates. Cells were stimulated with various concentrations of different IFNs in hydrocortisone-free medium. After 24 and 48 hours, IP10 and ET-1 were measured by ELISA in conditioned medium. In a second set of experiments, cells were pre-treated with tumour necrosis factor-α (TNF-α) (10 ng/mL). IFNα2a, IFNα2b, 40KDa-PEGIFNα2a and 12KDa-PEGIFNα2b, but not IFNλ, induced IP10 (CXCL10) release and increased IP10 gene induction in HLMVEC. In addition, all four IFNα preparations induced IP10 release from HPASM cells and A549 cells pre-treated with TNFα. In each of these cell types, 40KDa-PEGIFNα2a was significantly less active than the native forms of IFNα2a, IFNα2b or 12KDa-PEGIFNα2b. Similarly, IFNα2a, IFNα2b and 12KDa-PEGIFNα2b, but not 40KDa-PEGIFNα2a, induced endothelin (ET)-1 release from HPASM cells. Consistent with other interstitial pulmonary diseases, both IP10 and ET1 may serve as markers to monitor IFN-induced lung toxicity in patients. In addition, both markers may also serve to help characterize the risk associated with IFNα preparations to induce lung toxicity.