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Scientific Tracks Abstracts: JAA
Robust and rapid induction of interferon-ı (IFN-ı) in monocytes following pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes. We found that IFN-_ is produced rapidly in primary human monocytes as a result of co-operation between the myeloid-specifi c transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knock-down of IRF8 in monocytes abrogated IFN-ı transcription, while reintroduction of IRF8 into the IRF8-/- 32Dcl3 murine myeloid cell line reinstated IFN-ıııtranscription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element (EICE) of the IFN-ı promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-ı production, as a previously unindentifi ed interaction partner of IRF8. We mapped the protein-protein interacting regions of IRF3 and IRF8, and found that their interaction was independent of the DNA-binding domain (DBD) and the IRF association domain (IAD) of IRF8 and IRF3, respectively. Based on our data, we propose a model for the rapid induction of IFN-_ in monocytes, whereby IRF8 and PU.1 form a scaff old complex on the IFN-ı enhancer to facilitate the recruitment of IRF3, thus enabling rapid IFN-ı transcription.
Keh-Chuang Chin graduated in Biochemistry from the University of Iowa in 1996 and obtained his D. Phil in Biochemistry and Biophysics at the University of North Carolina at Chapel Hill 1997, where he did his studies on the transcriptional regulation of class II major histo-compatibility molecules (MHC-II) under the supervision of Dr. Jenny Ting. After post-doctoral work in Dr. Peter Cresswell?s lab (Howard Hughes Medical Institute, Section of Immunobiology, Yale University), he was appointed as Senior Research Scientist at the Genome Institute of Singapore in 2003. He joined SIgN in 2006.