Epidermal and Oral Keratinocytes Are Induced to Produce RANTES and IL-8 by Cytokine Stimulation

Abstract

RANTES, interleukin-8 (IL-8), and macrophage inflammatory protein-1-alpha (MIP-1 alpha) exhibit different and highly selective chemotactic activity for leukocytes. Resting cultured normal oral and skin keratinocytes produced little if any of these chemokines. Stimulation with 250-1,000 U/ml of tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) induced both cell types to produce RANTES. Protein levels peaked after 48 h and mRNA levels peaked after 8 h of stimulation. Used combination, TNF-alpha, and IFN-gamma synergistically increased mRNA and protein levels. Amounts of 100-1,000 U/ml of TNF-alpha also induced IL-8 production with peak mRNA levels after 4-24 h of stimulation and maximal protein production after 72 h or more. IL-8 production by oral keratinocytes was significantly greater than that by skin keratinocytes. Although IFN-gamma alone did not induce IL-8 production, it enhanced the effect of TNF-alpha on both cell types. Stimulation for 24 h with 100-1,000 U/ml of IL-alpha also induced IL-8 production by oral but not skin keratinocytes. No MIP-1 alpha production was detected under the conditions investigated. Keratinocyte production of RANTES and IL-8, under the influence of cytokines such as TNF-alpha or IFN-gamma, provides a mechanism for the selective accumulation of leukocytes into immunoinflammatory diseases of the skin and oral mucosa. Differences in their production may help to explain differences in the presentation of these diseases on the skin and oral mucosa.