Mesenchymal expression of nuclear factor-kappa B inhibits epithelial growth and branching in the embryonic chick lung

It is becoming increasingly recognized that the ubiquitous, inducible trans cription factor nuclear factor-kappa B (NF-kappa B) is involved in developm ental processes. For example, NF-kappa B acts as a mediator of epithelial-m esenchymal interactions in the developing chick limb. We investigated the r ole of NF-kappa B in directing the branching morphogenesis of the developin g chick lung, a process which relies on epithelial-mesenchymal communicatio n. High level expression of relA was found in the mesenchyme surrounding th e nonbranching structures of the lung but was not detected either in the me senchyme surrounding the branching structures of the distal lung or in the developing lung epithelium. Specific inhibition of mesenchymal NF-kappa B i n lung cultures resulted in increased epithelial budding. Conversely, expre ssion of a trans-dominant activator of NF-kappa B in the lung mesenchyme re pressed budding. Ectopic expression of RelA was sufficient to inhibit the a bility of the distal mesenchyme to induce epithelial bud formation. Cellula r proliferation in the mesenchyme was inhibited by hyperactivation of NF-ka ppa B in the mesenchyme of lung cultures. Interestingly, increased NF-kappa B activity in the mesenchyme also decreased the proliferation of the assoc iated epithelium, while inhibition of NF-kappa B activity increased cellula r proliferation in lung cultures. Expression patterns of several genes whic h are known to influence lung branching morphogenesis were altered in respo nse to changes in mesenchymal NF-kappa B activity, including fgf10, bmp-4, and tgf-beta 1. Thus NF-kappa B represents the first transcription factor r eported to function within the lung mesenchyme to limit growth and branchin g of the adjacent epithelium. (C) 2000 Academic Press.