Abstract
The potent vasoconstrictor and mitogen peptide endothelin-1 (ET-1) is a therapeutic target for the treatment of pulmonary hypertension. Work from our group has shown that ET-1 release by human pulmonary artery smooth muscle cells (HPASMCs) is critically regulated by interferons (IFN) and TNF. We have shown that type I IFNα and IFNβ and type II IFNγ, but not type III IFNλ, all released in host responses to viral infection, induce ET-1. As viral infection and IFN therapy are increasingly associated with lung toxicity, including pulmonary hypertension, we have investigated the nature of any interaction between IFNs for ET-1 release by HPASMCs. Cells from 3 separate donors were stimulated in 96-well plates with IFNα, -β, -γ and -λ (all 10ng/ml). Supernatants were collected after 24 hours and ET-1 concentrations measured by sandwich ELISA. In the presence of TNFα (10ng/ml), type I IFNs (-α and -β) or type II IFNγ, but not type III IFNλ, induced ET-1 release. Additive release of ET-1 was seen with IFNα/γ and IFNβ/γ but not IFNα/β. IFNλ did not release ET-1 under any condition studied. Type I and II IFNs act independently to stimulate ET-1 from HPASMCs, which reflects what is known about their separate receptor pathways.
Our finding that IFNλ is inactive in these cells may suggest that type III IFN spares the lung vasculature.
- © 2011 ERS