CYTOKINE INDUCTION IN HUMAN EPIDERMAL-KERATINOCYTES EXPOSED TO CONTACT IRRITANTS AND ITS RELATION TO CHEMICAL-INDUCED INFLAMMATION IN MOUSESKIN

In response to exogenous stimuli such as phorbol-12-myristate 13-aceta te, ultraviolet B radiation, and lipopolysaccharide, human keratinocyt es produce soluble mediators that are important in primary contact irr itancy including cytokines that are associated with proinflammatory pr operties (interleukin-1 alpha [IL-1 alpha], tumor necrosis factor alph a), chemotaxis (IL-8), and growth activation (granulocyte/macrophage c olony stimulating factor, IL-6, transforming growth factor alpha). We examined qualitative and quantitative changes in selected intracellula r and secreted cytokines in human keratinocyte cultures in response to non-sensitizing contact irritants (croton oil, sodium lauryl sulfate, methyl salicylate, ethyl phenylpropiolate), sensitizing irritants (ox azolone, dinitrofluorobenzene), and ulcerative agents (phenol, benzalk onium chloride, chromium trioxide). The chemicals were also applied to mouse skin to assess whether the chemical-specific pattern of inflamm ation correlated with the in vitro production of keratinocyte-derived cytokines. Although all agents elicited neutrophils to the site of che mical application, time dependent and chemical-specific patterns of in flammation could be detected. Sodium lauryl sulfate, phenol, and croto n oil induced increases in IL-8 production at noncytotoxic concentrati ons in semi-confluent human keratinocyte cultures. Phenol and croton o il stimulated tumor necrosis factor a production, whereas croton oil w as the only agent found to induce granulocyte/macrophage colony-stimul ating factor production. Croton oil, phenol, benzalkonium chloride, an d dinitrofluorobenzene induced the intracellular production of IL-1 al pha without a concomitant release into the medium. The release of cyto kines occurred in parallel with a relative increase in cytokine-specif ic mRNA transcripts. Studies using neutralizing antibodies to tumor ne crosis factor alpha and IL-1 alpha demonstrated that IL-8 induction by croton oil and phenol occurred directly rather than through autocrine circuits. These data suggest that a given pattern of cytokine product ion is chemical-specific and may predict the contribution of keratinoc ytes to skin inflammation.