Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity

Area of Science:

• Developmental Biology
• Immunology
• Molecular Biology

Background:

• The dorsal transcription factor regulates twist during Drosophila embryogenesis.
• Twist proteins are crucial for mesoderm formation.
• Cytokine signaling pathways play vital roles in development and immunity.

Purpose of the Study:

• To investigate the role of mammalian twist proteins (twist-1 and -2) in cytokine signaling.
• To elucidate the regulatory relationship between twist proteins and the NF-kappaB pathway.
• To understand the in vivo consequences of twist protein dysregulation.

Main Methods:

• Investigated induction of twist-1 and twist-2 by cytokine signaling.
• Examined the interaction between twist proteins and RelA (a member of the NF-kappaB family).
• Utilized mouse models with null or heterozygous twist-2 and twist-1 alleles.

Main Results:

• Mammalian twist-1 and -2 are induced by a cytokine signaling pathway involving RelA.
• Twist-1 and -2 repress cytokine gene expression via interaction with RelA.
• Mice lacking functional twist-2 or with reduced twist-1/twist-2 exhibit elevated proinflammatory cytokines and perinatal lethality due to cachexia.

Conclusions:

• Twist proteins are key regulators of cytokine signaling through a conserved negative feedback loop.
• This feedback loop involves the repression of NF-kappaB-dependent cytokine pathways.
• Dysregulation of this twist-NF-kappaB circuit has severe developmental and physiological consequences.