Epidermal growth factor and transforming growth factor‐alpha decrease gamma interferon receptors and induction of intercellular adhesion molecule (ICAM‐1) on cultured keratinocytes

The link between the epidermal keratinocytes of the skin and the activated T lymphocytes of the immune system is mediated by a variety of cytokines, including gamma interferon (IFN‐γ). We studied the influence of keratinocyte mitogens such as transforming growth factor‐alpha (TGF‐α), epidermal growth factor (EGF), and somatomedin‐C (SM‐C) on the ligand binding of 32 P‐labelled IFN‐γ to cultured keratinocytes derived from normal appearing adult human skin. Keratinocytes placed in a medium devoid of mitogens become growth arrested, and these quiescent cells expressed 2.4 times (28,900 versus 12,200 sites/cell) as many high affinity IFN‐γ receptors (Kd = 0.22 nM) compared to keratinocytes which were actively growing in medium containing TGF‐α (25 ng/ml) or EGF (10 ng/ml). The reduction in IFN‐γ receptor sites by TGF‐α/EGF was mitogen specific, as adding SM‐C (500 ng/ml) did not have any effect on ligand binding, although it similarily stimulated keratinocyte growth. The reduction in IFN‐γ receptors was time dependent, occurring primarily after 24–48 hours of change in tissue culture conditions. The reduction in the number of high affinity IFN‐γ receptors by TGF‐α/EGF had immunobiological consequences, because quiescent keratinocytes in basal medium had an increased expression of HLA‐DR and intercellular adhesion molecule‐1 (ICAM‐1) induced by IFN‐γ, compared to actively growing TGF‐α/EGF treated keratinocytes. These results suggest that rapidly proliferating keratinocytes exposed to TGF‐α/EGF but not SM‐C are capable of altering their response to IFN‐γ by decreasing their number of cell surface high affinity receptors for IFN‐γ.