Decreased growth inhibition by recombinant gamma interferon is associated with increased transforming growth factor-α production in keratinocytes cultured from psoriatic lesions

Publisher Website
Google Scholar
Abstract
Keratinocytes from involved psoriatic plaques (PP), uninvolved, clinically symptomless skin of psoriatic patients (PN) and normal healthy skin (NN) have been cultured in a low calcium serum free system for multiple passages. In this way, the keratinocytes were removed from microenvironmental factors present in the skin. While the basal rate of proliferation of the PP, PN and NN keratinocytes was not different, the PP cells produced more transforming growth factor-.alpha. (TGF-.alpha.) than NN cells, and the antiproliferative response of PP cells to gamma interferon (IFN-.gamma.), a product of activated T lymphocytes, was reduced. We studied IFN-.gamma. because it can inhibit the proliferation of NN keratinocytes, induce their differentiation and the appearance of two immunoregulatory cell surface molecules, HLA-DR and intercellular adherence molecule-I (ICAM-I), and because in another epithelial cell system, epidermal growth factor (EGF) modulates IFN-.gamma. activity. The mean antiproliferative effects of IFN-.gamma. at 50, 200, and 500 U/ml for the PP group (n = 10) was less compared to the NN group (n = 11); P < 0.001, while the PN group (n = 5) had a less dramatic, but statistically significant, reduction in growth inhibition by IFN-.gamma. only at 200 and 500 U/ml compared to NN cells; P < 0.05 and P < 0.01, respectively. The amount of TGF-.alpha. produced and secreted by PP keratinocytes from five different individuals was significantly greater than by NN keratinocytes cultures. In addition, IFN-.gamma. induced TGF-.alpha. to a lesser extent in PP keratinocytes compared to NN keratinocyte cultures. Keratinocytes isolated from atopic dermatitis and Sezary syndrome patients were similar to NN keratinocytes. In contrast to its differential effects of TGF-.alpha. production and proliferation, IFN-.gamma. induced similar amounts of HLA-DR and ICAM-I on PP, PN and NN keratinocytes. Thus, for the PP keratinocytes, there was a dissociation between the antiproliferative and immunomodulatory effects of IFN-.gamma.. These results support our previous hypothesis that the hyperproliferation and altered differentiation of keratinocytes in psoriatic plaques is linked to an altered responsiveness of the keratinocytes to IFN-.gamma.. Moreover, these results provide an in vitro correlate of our in vivo observation of increased TGF-.alpha. levels in psoriatic plaques. A new pathophysiological model to understand psoriasis is proposed which integrates these observations involving IFN-.gamma. and TGF-.alpha.. This experimental approach also provides a system to dissect biochemical pathways of pathophysiological importance for keratinocyte hyperproliferation in psoriasis.