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Oscillatory Control of Interferon Regulatory Factor 3

Innate immune responses to pathogen exposure are coordinated by two transcription factors, Nuclear Factor‐kappaB (NF‐κB) and Interferon Regulatory Factor 3 (IRF3). Prior work has established that NF‐κB activity shows complex temporal dynamics, and several inflammatory stimuli trigger oscillations of its nuclear activity. Indeed, oscillatory control of NF‐κB has been a focus for the research community to understand the underlying negative feedback control by IκBα and its physiological function. To our surprise, recent studies in our laboratory have revealed that IRF3 is also oscillatory in response to lipopolysaccharide (LPS) stimulation. However, those preliminary studies employed an overexpressed GFP‐IRF3 fusion protein. In this study, we sought to determine whether the endogenous IRF3 also shows oscillatory dynamics or whether the prior observation may be an artifact of the exogenous fusion protein. To this end cytosolic and nuclear fractions were collected from macrophages and Western Blots were performed. After improving the reliability of the Western blot protocol our data confirm the single cell results in that IRF3 is rapidly translocated to the nucleus within 30 min following LPS stimulation, is then exported back to the cytoplasm by 90 min, and relocated to the nucleus by 2 hrs. The importance of this finding is that it suggests the hypothesis that different stimuli may trigger different IRF3 oscillatory dynamics that may result in different innate immune responses. Future studies will address that hypothesis.