Acetaminophen Modulates the Transcriptional Response to Recombinant Interferon-β

Aaron Farnsworth,Carole L Yauk,Anathea S Flaman,Xuguang Li,Shiv S Prasad,Caroline Gravel,Andrew Williams,Yuan Luo

doi:10.1371/journal.pone.0011031

Abstract

BackgroundRecombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration.Methodology/Principal FindingsWe tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-β treatment. CD-1 mice were administered acetaminophen (APAP), interferon-β (IFN-β) or a combination of IFN-β+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-β. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IκBK/NF-κB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points.Conclusions/SignificanceA significant change in the transcriptional response was observed following co-administration of IFN-β+APAP relative to IFN-β treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-β treatment.

Highlights

Type I interferons (IFNs) are key cytokines in the activation of the innate immune response and induce a cascade of anti-viral, anti-proliferative and immunomodulatory responses
Experimental Design Pilot studies were conducted in which mice were treated with varying doses of APAP or IFN-b (APAP 100–550 mg/kg, IFN-b 16106–16108 U/kg) and liver and sera were collected at several time points (1.5–24 h)
There was some clustering within time points, but the analysis revealed that APAP causes very little change in overall gene expression, while IFN-b and IFN-b+APAP treatments induce similar changes in transcript levels

Summary

Introduction

Type I interferons (IFNs) are key cytokines in the activation of the innate immune response and induce a cascade of anti-viral, anti-proliferative and immunomodulatory responses (as reviewed in [1,2]). Type I interferons signal through the coordinated activation of Janus (JAK) family kinases and Signal Transducers and Activator of Transcription (STAT) family members. IFN-mediated signal transduction begins when the IFN Alpha receptor (IFNAR) is dimerized by IFN, resulting in auto-phosphorylation of receptor-associated JAK tyrosine kinases. Phosphorylated JAKs activate associated STAT proteins which translocate to the nucleus where they induce transcription through binding to different promoter elements. Beyond the induction of transcription through IFN activity the convergence of signals with other pathways such as the IkK/NF-kB can modify the transcriptional response. Little is known regarding the transcriptional changes induced by such co-administration

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