Unique Keratinocyte-Specific Effects of Interferon-γ that Protect Skin from Viruses, Identified Using Transcriptional Profiling

Abstract

Interferon (IFN)-γ, is a multifunctional, immunomodulatory cytokine with cell type-specific antiviral activities, particularly important in skin, where it is implicated in many diseases ranging from warts to psoriasis and cancer. Since epidermis is our first line of defence against many viruses, we investigated the molecular processes regulated by IFN-γ in keratinocytes using DNA microarrays. We identified the IFN-γ-regulated keratinocyte-specific genes and antiviral processes. Exclusively in keratinocytes, IFN-γ-induced tight junction proteins, presumably to deny viruses paracellular routes of infection. Furthermore, differing from published data, we find that IFN-γ suppressed the expression of keratinocytes differentiation markers including desmosomal proteins, cornified envelope components and suprabasal cytokeratins. Inhibition of differentiation may interfere with the epidermal tropism of viruses that require differentiating cells for growth, for example, papillomaviruses. As in other cell types, IFN-γ induced HLA, cell adhesion and proteasome proteins, facilitating leukocyte attraction and antigen-presentation by keratinocytes. IFN-γ also induced chemokine/cytokines specific for mononuclear cells. IFN-γ suppressed the expression of over 100 genes responsible for cell cycle, DNA replication and RNA metabolism, thereby shutting down many nuclear processes and denying viruses a healthy cell in which to replicate. Thus, uniquely in keratinocytes, IFN-γ initiates a well-organized molecular programme boosting host antiviral defences, obstructing viral entry, suppressing cell proliferation and impeding differentiation.