Twist-2 controls myeloid lineage development and function.
Basic helix-loop-helix (bHLH) transcription factors play critical roles in lymphoid and erythroid development; however, little is known about their role in myeloid lineage development. In this study, we identify the bHLH transcription factor Twist-2 as a key negative regulator of myeloid lineage development, as manifested by marked increases in mature myeloid populations of macrophages, neutrophils, and basophils in Twist-2-deficient mice. Mechanistic studies demonstrate that Twist-2 inhibits the proliferation as well as differentiation of granulocyte macrophage progenitors (GMP) by interacting with and inhibiting the transcription factors Runx1 and C/EBPalpha. Moreover, Twist-2 was found to have a contrasting effect on cytokine production: inhibiting the production of proinflammatory cytokines such as interleukin-12 (IL-12) and interferon-gamma (IFNgamma) while promoting the regulatory cytokine IL-10 by myeloid cells. The data from further analyses suggest that Twist-2 activates the transcription factor c-Maf, leading to IL-10 expression. In addition, Twist-2 was found to be essential for endotoxin tolerance. Thus, this study reveals the critical role of Twist-2 in regulating the development of myeloid lineages, as well as the function and inflammatory responses of mature myeloid cells.
Sharabi
Andrew B
AB
Department of Immunology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
Aldrich
Melissa
M
Sosic
Drazen
D
Olson
Eric N
EN
Friedman
Alan D
AD
Lee
Sung-Hyung
SH
Chen
Si-Yi
SY
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000502:physiology*
D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; D004731:Endotoxins; C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D012097:Repressor Proteins; C493726:Runx1 protein, mouse; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma