Interferon regulatory factor-8−driven myeloid differentiation is regulated by 12/15-lipoxygenase−mediated redox signaling

Kinder, Michelle; Thompson, James E.; Wei, Cong; Shelat, Suresh G.; Blair, Ian A.; Carroll, Martin; Puré, Ellen

doi:10.1016/j.exphem.2010.07.004

« Previous Next »Experimental Hematology
Volume 38, Issue 11 , Pages 1036-1046.e4, November 2010

Interferon regulatory factor-8−driven myeloid differentiation is regulated by 12/15-lipoxygenase−mediated redox signaling

Michelle Kinder
- The Wistar Institute, Philadelphia, Pa., USA
- Immunology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
James E. Thompson
- Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pa., USA
- Current address: Departments of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Cong Wei
- Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pa., USA
Suresh G. Shelat
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pa., USA
Ian A. Blair
- Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pa., USA
Martin Carroll
- Immunology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
- Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pa., USA
Ellen Puré
- The Wistar Institute, Philadelphia, Pa., USA
- Immunology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
- Offprint requests to: Ellen Puré, Ph.D., The Wistar Institute, 3601 Spruce Street, Room 372, Philadelphia, PA 19104

Received 19 January 2010; received in revised form 18 June 2010; accepted 9 July 2010. published online 21 July 2010.

Objective

Several transcription factors determine the cell fate decision between granulocytes and monocytes, but the upstream signal transduction pathways that govern myelopoiesis are largely unknown. Based on our observation of aberrant myeloid cell representation in hematopoietic tissues of 12/15-lipoxygenase (12/15-LOX)-deficient (Alox15) mice, we tested the hypothesis that polyunsaturated fatty acid metabolism regulates myelopoiesis.

Materials and Methods

Multicolor flow cytometric analysis and methylcellulose assays were used to compare myelopoiesis and the differentiative capacity of progenitors from Alox15 and wild-type mice. Furthermore, we elucidated the mechanism by which 12/15-LOX is involved in regulation of myelopoiesis.

Results

Granulopoiesis in Alox15 mice is increased while monopoiesis is reduced. Moreover, there is an accumulation of granulocyte-macrophage progenitors that exhibit defective differentiation. Mechanistically, we demonstrate that transcriptional activity of interferon regulatory factor-8 (Irf8), which regulates myelopoiesis, is impaired in Alox15 progenitors and bone marrow-derived macrophages due to loss of 12/15-LOX-mediated redox regulation of Irf8 nuclear accumulation. Restoration of redox signaling in Alox15 bone marrow cells and granulocyte-macrophage progenitors reversed the defect in myeloid differentiation.