Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-beta production by fibroblasts.

The TSK/TSK mutation is embryonic lethal; embryos have been reported to die at 7-8 days of gestational age. Crossing TSK/+, IL-4+/- mice revealed that disrupting one or both IL-4 alleles allowed survival of 29 and 47%, respectively, of TSK/TSK mice. These mice failed to develop cutaneous hyperplasia but did exhibit the emphysema that is found in TSK/+ mice. We showed that IL-4 stimulation of fibroblasts increased the level of transforming growth factor-beta (TGF-beta) mRNA and that lungs of TSK/+, IL-4-/- mice had substantially less TGF-beta mRNA than lungs of TSK/+, IL-4+/+ mice. Thus IL-4 seems to regulate the expression of TGF-beta in fibroblasts, providing an explanation for the absence of cutaneous hyperplasia in TSK/+, IL-4Ralpha-/- and TSK/+, TGF-beta+/- mice.