Role of receptor complexes in resistance or sensitivity to growth inhibition by TGF beta in intestinal epithelial cell clones.

Untransformed rat intestinal epithelial cells (IEC-18) were chemically mutagenized, selected in the presence of TGF beta 1, and cloned by limiting dilution. Two clones (4-5, 4-6) were resistant to growth inhibition by both TGF beta 1 and TGF beta 2. Another clone (4-1) was more sensitive to both TGF beta isoforms (relative to parental IEC-18 cells). IC50 values for TGF beta 1 and 2 in the 4-1 cells were at least 1/9 those of the parental cells; growth rates were reduced by 49% for TGF beta 1 and by 26% for TGF beta 2 in this clone. This increased sensitivity to TGF beta was explained by the 5- to 10-fold increase, relative to parental cells, in binding of TGF beta 1 and TGF beta 2 to both the type I and II receptors. In contrast, the resistance to growth inhibition by TGF beta in the 4-5 and 4-6 cells could not be explained by a decrease in either TGF beta binding affinities or in total number of receptors expressed, by the presence of serum binding components, or by occupation of receptor binding sites with autocrine TGF-beta 1. However, in comparison to TGF beta-sensitive cells (IEC-18, 4-1), the resistant cells displayed a higher ratio of type II relative to type I receptor binding by TGF-beta 1. Thus, a critical ratio of binding to receptor subtypes correlated with growth inhibition by TGF-beta 1. Resistance to TGF-beta 2 in the same clones did not appear to be receptor related. Thus, different mechanisms for resistance to TGF-beta 1 and TGF-beta 2 were observed within a given clone.