Abstract
BackgroundHepcidin serves as a major regulator of systemic iron metabolism and immune function. Airway epithelial cells have an extensive interface with the environment, and so must be able to respond locally to the presence of particulates, infection, and inflammation. Therefore, we hypothesized that hepcidin is expressed in airway epithelial cells and is regulated by early phase cytokines.MethodsPrimary, differentiated human bronchial epithelial (NHBE) cells were used to assess hepcidin gene expression in response to IFN-γ, TNF-α, IL-1β, and IL-6, as well as to LPS + CD14. The role of the Janus Kinase-signal transducer and activator of transcription (JAK-STAT) pathway in IFN-γ-mediated hepcidin production was assessed by measuring JAK2 phophorylation and STAT1 nuclear translocation. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine whether hepcidin altered iron transport in either NHBE cells or primary alveolar macrophages.ResultsWe demonstrate that differentiated human airway epithelial cells express hepcidin mRNA and that its expression is augmented in response to IFN-γ via activation of STAT1. However, while IFN-γ induced hepcidin gene expression, we were not able to demonstrate diminished expression of the iron export protein, ferroportin (Fpn), at the cell surface, or iron accumulation in airway epithelial in the presence of exogenous hepcidin.ConclusionThese data demonstrate that airway epithelial cells express hepcidin in the lung in response to IFN-γ. The presence of hepcidin in the airway does not appear to alter cellular iron transport, but may serve as a protective factor via its direct antimicrobial effects.
Highlights
Hepcidin serves as a major regulator of systemic iron metabolism and immune function
Hepcidin is expressed in airway epithelial cells and is regulated by IFN-g To determine whether hepcidin is expressed locally in airway epithelial cells and is regulated in response to pro-inflammatory stimuli, we exposed differentiated NHBE cells to LPS (100 μg/ml) and CD14 (250 ng/ml) [21], or to a mixture of pro-inflammatory cytokines (cytomix: TNF-a, IL-1b and IFN-g (100 ng/ml each))
Because iron metabolism in the lung requires coordination between epithelial cells and macrophages [25], we evaluated whether hepcidin released by airway epithelial cells could impact iron transport in NHBE cells or alveolar macrophages
Summary
Hepcidin serves as a major regulator of systemic iron metabolism and immune function. Hepcidin is expressed in numerous cell types including macrophages, myocytes, and neurons, where it responds in a tissue specific manner to alterations in iron content, changes in oxygen tension, and the presence of inflammation [1,7,9,10,11]. Hepcidin modulates immune function in part by its ability to decrease iron absorption and serum iron content in response to infection and inflammation in order to reduce the iron available to pathogens. Antimicrobial peptides serve as an important component of the innate immune system and are predominantly expressed at epithelial surfaces where interactions with the outside environment exist and constitute the first line of defense against invading pathogens [16]
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