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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Cardiothoracic Pharmacology, National Heart and Lung Institute (NHLI), Imperial College, London, United Kingdom.
Rekha
R
Badiger
Jane A
JA
Mitchell
Hime
H
Gashaw
Neil A
NA
Galloway-Phillipps
Stefan
S
Foser
Fernando
F
Tatsch
Thomas
T
Singer
Trevor T
TT
Hansel
Tobias
T
Manigold
D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008168:Lung / Q000166:cytology*; D018121:Receptors, Cytokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
D019332:Endothelin-1; C104577:IP10-Mig receptor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D018121:Receptors, Cytokine; D011994:Recombinant Proteins