Cytokine effects on human keratinocyte growth and characterization of a novel protein tyrosine phosphatase

Abstract

The effects of IL-4 on the proliferation of normal human keratinocytes in vitro were studied. Proliferation of keratinocytes was stimulated by IL-4 and neutralized by the treatment of anti-IL-4 antibody. Anti-IL-6 antibody did not inhibit the proliferation of normal human keratinocytes, suggesting that the IL-4 is directly responsible for the keratinocyte proliferation. The IL-4 significantly induced cell cycle progression from G0/G1 to S phase. The keratinocyte proliferation by IL-4 appeared to be mediated through a growth control gene, c-myc proto-oncogene. The c-myc mRNA expression was significantly increased after the IL-4 treatment of keratinocytes, suggesting that c-myc gene expression plays a key role in the control of keratinocyte proliferation. The signal transduction pathways induced by IL-4 in the keratinocytes were also studied using chemicals that can intervene in certain signal transduction events. Genistein, a tyrosine kinase inhibitor, suppressed c-myc mRNA expression induced by IL-4. H7, a serine/threonine kinase inhibitor, and okadaic acid, a protein phosphatase 1 and 2A inhibitor, however, did not block the c-myc gene expression. These results suggest that IL-4 stimulates the proliferation of keratinocytes in vitro by promoting a cell cycle transition from G0/G1 to S phase. The induction of c-myc after IL-4 treatment implicates an important role of c-myc in the proliferation of keratinocytes. The data also suggest an important role of tyrosine kinases on the IL-4-induced proliferation of keratinocytes. Tyrosine phosphorylation and dephosphorylation of cellular proteins have been suggested to play important roles in cellular signaling and many other cellular activities. After the search of protein tyrosine phosphatases expressed in human keratinocytes, a human homologue of the murine R-PTP-k (human R-PTP-k) has been cloned. Amongst the several overlapping cDNA clones, one clone was found to encode a full length of human R-PTP-k. The human R...