IFN-gamma regulation of ICAM-1 receptors in bronchial epithelial cells: soluble ICAM–1 release inhibits human rhinovirus infection

Suzanne C Whiteman,Monica A Spiteri

doi:10.1186/1476-9255-5-8

Abstract

BackgroundIntercellular adhesion molecule-1 (ICAM-1) is a critical target-docking molecule on epithelial cells for 90% of human rhinovirus (HRV) serotypes. Two forms of ICAM-1 exist, membranous (mICAM-1) and soluble (sICAM-1), both expressed by bronchial epithelial cells. Interferon-gamma (IFN-γ), a crucial Th-1 immuno-regulatory mediator, can modulate mICAM-1 expression; however its simultaneous effects on mICAM-1: sICAM-1 levels and their consequent outcome on cell infectivity have not been previously explored.MethodsPrimary normal human bronchial epithelial cells were pre-stimulated with IFN-γ (1 ng/ml for 24 h) and subsequently inoculated with HRV-14 or HRV-1b (TCID50 10 2.5). Epithelial surface ICAM-1 expression and soluble ICAM-1 release were measured at the protein and gene level by immunofluorescence and ELISA respectively; mRNA levels were semi-quantified using RT-PCR. Molecular mechanisms regulating ICAM-1 isoform expression and effects on epithelial cell infectivity were explored.ResultsIn IFN-γ-biased cells infected with HRV-14, but not HRV-1b, mICAM-1 expression is down-regulated, with simultaneous induction of sICAM-1 release. This differential effect on HRV-14 receptor isoforms appears to be related to a combination of decreased IFN-γ-induced JAK-STAT signalling and proteolytic receptor cleavage of the membranous form in IFN-γ-biased HRV-14 infected cells. The observed changes in relative mICAM-1: sICAM-1 expression levels are associated with reduced HRV-14 viral titres.ConclusionThese findings support the hypothesis that in epithelial cells conditioned to IFN-γ and subsequently exposed to HRV-14 infection, differential modulation in the ratio of ICAM-1 receptors prevails in favour of an anti-viral milieu, appearing to limit further target cell viral attachment and propagation.

Highlights

Intercellular adhesion molecule-1 (ICAM-1) is a critical target-docking molecule on epithelial cells for 90% of human rhinovirus (HRV) serotypes
Down-regulation of mICAM-1 expression: response to IFNγ and HRV infection The present authors describe first the effects of the Th-1 mediator IFN-γ on expression behaviour of mICAM-1 isoform in normal human bronchial epithelial cells (NHBE) cells, and how expression was altered in the presence of HRV infection
Observed patterns of expression were consistent across the different source NHBE cultures. mICAM-1 protein did not change in control untreated, uninfected cells throughout the test 96 h culture period (Fig. 1A)

Summary

Introduction

Intercellular adhesion molecule-1 (ICAM-1) is a critical target-docking molecule on epithelial cells for 90% of human rhinovirus (HRV) serotypes. Two distinct forms of ICAM-1 receptor have been identified, membrane bound (mICAM-1) and soluble (sICAM1) [1]; both are expressed by airway epithelial cells (EC). The present authors previously demonstrated that HRV selectively manipulates epithelial cell mICAM-1 and sICAM-1 expression in an inverse fashion to effect airway epithelial cell infection and promote/propagate viral respiratory episodes [2]. The present authors have demonstrated that IFN-γ induces down-regulation of mICAM-1 expression in HRV-14- infected cells with consequent decrease in viral titres and cell infection [14]. The present authors hypothesise that IFN-γ biased cells exposed to HRV-14 may selectively modulate own ICAM-1 receptor levels, promoting a down-regulation of mICAM-1 expression, whilst inducing sICAM-1 release into the local milieu. SICAM1 has been shown to possess anti-viral properties both in vitro [15] and in vivo [16,17]

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Results

Conclusion