TGF-βRII Rescues Development of Small Intestinal Epithelial Cells in Elf3-Deficient Mice

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…[27][28][29] Interestingly, ectopic expression of the human TGF-b RII transgene specifically in the intestinal epithelium of Elf3À/À mice can rescue the previously characterized intestinal defects of Elf3À/À mice. 30 This phenotypic rescue provides further in vivo evidence that Elf3 is the critical upstream regulator of TGF-b RII expression in the mouse small intestinal epithelium. 30 In addition, we have previously shown reduced expression of the proinflammatory cytokine, interleukin-6 (IL-6), in the lungs of Elf3À/À mice when compared with their wild-type littermates after intranasal instillation of lipopolysaccharide, 31 suggesting a possible role for Elf3 in the regulation of IL-6 expression.…”

“…30 This phenotypic rescue provides further in vivo evidence that Elf3 is the critical upstream regulator of TGF-b RII expression in the mouse small intestinal epithelium. 30 In addition, we have previously shown reduced expression of the proinflammatory cytokine, interleukin-6 (IL-6), in the lungs of Elf3À/À mice when compared with their wild-type littermates after intranasal instillation of lipopolysaccharide, 31 suggesting a possible role for Elf3 in the regulation of IL-6 expression. Both TGF-b RII (see Zhao et al 32 ) and IL-6 (see Kida et al 33 ) have also been shown to be involved in the process of lung injury and repair.…”

“…However, Elf3 has been shown to be involved in regulating the expression of genes involved in controlling epithelial cell proliferation and differentiation during embryonic/fetal development and oncogenesis. 17,26,30,37,38,[42][43][44] Therefore, the delayed kinetics of cell proliferation/mitosis and Clara cell reconstitution observed within the bronchiolar airway epithelium of Elf3À/À mice is more likely because of changes in gene expression for proteins involved in regulating epithelial cell proliferation and/or differentiation during repair after naphthalene-induced Clara cell ablation. The best known candidate is the gene encoding for TGF-b RII, as several studies have clearly shown that Elf3 can bind to the promoter and regulate transcription of the TGF-b RII gene.…”

“…26 Although TGF-b RII is a potent inhibitor of cell proliferation, it is very important for the induction of epithelial cell differentiation. 26,30 Interestingly, Elf3À/À mice also exhibit defective terminal differentiation of the small intestinal epithelium during fetal/neonatal development. 26,30 In our study, we found that TGF-b RII levels were significantly lower within the bronchiolar airway epithelium of Elf3À/À mice than within that of Elf3 þ / þ mice during both the steady-state and regeneration after naphthalene injury.…”

“…26,30 Interestingly, Elf3À/À mice also exhibit defective terminal differentiation of the small intestinal epithelium during fetal/neonatal development. 26,30 In our study, we found that TGF-b RII levels were significantly lower within the bronchiolar airway epithelium of Elf3À/À mice than within that of Elf3 þ / þ mice during both the steady-state and regeneration after naphthalene injury. In addition, TGF-b RII levels in Elf3 þ / þ mice were significantly higher at day 14 post naphthalene injection than their respective steady-state control (day 0 and corn oil) levels, suggesting that expression of TGF-b RII is induced during repair and differentiation (occurring around day 14) of the injured airway epithelium and that TGF-b signaling may play an important role in this process.…”