Epidermal growth factor primes intestinal epithelial cells for proliferative effect of insulin-like growth factor I

Insulin-like growth factor I (IGF-I) synergistically enhances epidermal growth factor (EGF) -stimulated proliferation of intestinal epithelial cells. A possible mechanism of this synergy is that EGF acts as a "competence" factor increasing the fraction of proliferating cells by promoting transition from G₀ to G₁, thus allowing IGF-I, a "progression" factor, to act as a proliferative agent on the cycling population. Consistent with this hypothesis would be temporally distinct actions wherein initial brief exposure to EGF would permit synergy, whereas pretreatment with IGF-I would not. Rat intestinal epithelial cells of the IEC-18 crypt cell line were serum-deprived, then treated with EGF (5×10^-9 M), IGF-I (5×10^-9 M), or insulin (2×10^-6 M) for a 30-min pulse and then media containing EGF, IGF-I, insulin, or no factor was substituted for 48 hr. IGF-I and EGF each stimulated enterocyte proliferation; together they synergistically promoted cell growth. A brief pulse of IGF-I neither induced cell proliferation nor enhanced the EGF effect. Initial brief exposure to EGF, however, was equally efficacious as continuous exposure and allowed full synergy with IGF-I. Insulin at supraphysiologic levels acted similarly to IGF-I. Thus, EGF acted as a competence factor priming the cells for subsequent action by IGF-I. The cell kinetic parameters of these growth factors may be important to both physiologic and pathologic enterocyte growth regulation.