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Published online before print October 20, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0704429

Received for publication July 29, 2004.
Revised September 15, 2004.
Accepted for publication September 30, 2004.

Article

JAK2 is necessary and sufficient for interferon--induced transcription of the gene encoding gp91^PHOX

Renu Kakar ^*, Bryan Kautz ^*, and Elizabeth A. Eklund ^@

The Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and Jesse Brown VA Medical Center, Chicago Lakeside Division, Illinois; and *Birmingham Veteran’s Administration Hospital, Alabama

^@ To whom correspondence should be addressed. E-mail: e-eklund{at}northwestern.edu.

	Abstract

During the inflammatory response, interferon- (IFN-) increases transcription of the gene encoding gp91^PHOX, a respiratory burst oxidase component. This gene (referred to as the CYBB gene) is transcribed in phagocytic cells differentiated beyond the promyelocyte stage, and transcription continues until cell death. Previous investigations identified a positive regulatory element in the proximal CYBB promoter referred to as the hematopoiesis-associated factor 1 (HAF1)-cis element. This element is activated by a multiprotein complex, which includes the IFN consensus sequence-binding protein (ICSBP). Interaction of this complex with the HAF1-cis element requires ICSBP tyrosine phosphorylation, which is induced by IFN- stimulation of phagocytic cells. Previous studies also identified a negative cis element in the CYBB promoter. This element is repressed by the homeodomain protein HoxA10. HoxA10 tyrosine phosphorylation, which occurs in response to IFN-, decreases HoxA10 DNA binding and therefore repression of CYBB transcription. In these studies, we determine Janus tyrosine kinase 2 (JAK2) activation is necessary and sufficient for IFN--induced CYBB transcription in phagocytic cells and also for ICSBP and HoxA10 tyrosine phosphorylation. Consistent with these results, we find JAK2 activation is sufficient to induce ICSBP interaction with the HAF1 element and abolish HoxA10 binding to the CYBB repressor element. Therefore, these findings provide direct demonstration of JAK2 dependence of IFN--induced CYBB transcription. In addition, these results identify a mechanism mediating this effect.

Key Words: respiratory burst • interferon regulatory factor • Hox protein • CYBB gene • phagocyte function • neutrophil • monocyte

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