Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

ABSTRACT

Interferons (IFNs) are a family of immunoregulatory cytokines with important roles in anti-viral and anti-tumor responses. Type I and II IFNs bind distinct receptors and are associated with different stages of the immune response. There is however, considerable crosstalk between these two cytokines with enhancement of IFNγ responses following IFNα/β priming and loss of IFNα/β receptor (IFNAR) resulting in diminished IFNγ responses. In this study, we sought to define the mechanism of crosstalk between the type I and II IFNs. Our previous reports demonstrated reduced expression of the canonically activated transcription factor signal transducer and activator of transcription (STAT)1, in cells lacking the IFNAR α chain (IFNAR1). Therefore, we used microarray analysis to determine whether reconstitution of STAT1 in IFNAR1-deficient cells was sufficient to restore IFNγ responses. We identified several biological pathways, including the MHC class I antigen presentation pathway, in which STAT1 reconstitution was able to significantly rescue IFNγ-mediated gene regulation in Ifnar1^−/− cells. Notably, we also found that in addition to low basal expression of STAT1, cells lacking the IFNAR1 also had aberrant expression of multiple other transcription factors and signaling intermediaries. The studies described herein demonstrate that basal and regulated expression of signaling intermediaries is a mechanism for crosstalk between cytokines including type I and II IFNs.

KEYWORDS:

• cross talk
• gene expression
• interferon
• priming
• signal transduction
• STAT1
• transcription factors

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

ACKNOWLEDGMENTS

We thank Natalie Thomson for bioinformatics analysis and QC of microarray data. We also thank Dr Edwin Hawkins, Dr Sabine Hoves and Linda Hii for technical help.

Funding

The research reported in this publication was supported by the Cancer Research Institute (CRI scholarship), a Program Grant from the National Health and Medical Research Council of Australia (NHMRC) and a project grant from the Cancer Council Victoria. RWJ is an NHMRC Senior Principal Research Fellow.