EFFECTS OF TNF-α AND IL-1β ON THE ACTIVATION OF GENES RELATED TO INFLAMMATORY, IMMUNE RESPONSES AND CELL DEATH IN IMMORTALIZED HUMAN HaCat KERATINOCYTES

The present experiments were designed to characterize by microarray analysis the transcriptional responses of human keratinocytes (HaCat) to TNF-alpha and IL-1 beta, given alone or in combination, in order to better understand the mechanisms underlying inflammatory, immune responses and cell death in which both cytokines play a pathophysiological role. Significant differences in the percentage and quality of genes dysregulated by TNF-alpha and IL-1 beta were shown. Both cytokines activated a series of genes involved in inflammatory, immune response as well as in cell death. In our experimental conditions, TNF-alpha, in contrast to IL-1 beta, did not induce a significant level of apoptosis in keratinocytes. However, given together both cytokines produced a significant decrease in apoptotic cells and synergistic transcriptional response which was due to the activation of several specific genes occurring after application of each cytokine. TNF-alpha and IL-1 beta evoked apoptotic effect and transcriptional responses were linked to the stimulation of their specific receptors since a pre-treatment with monoclonal antibodies vs TNF-alpha and/or IL-1 beta receptors was able to significantly reduce them.