Keratinocytes play a crucial role in the regulation of skin
inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screening of the activities of 36
cytokines on keratinocyte gene expression identified
IL-17A,
IL-22,
oncostatin M,
TNF-alpha, and IL-1alpha as potent
cytokines in inducing cutaneous
inflammation. These five proinflammatory
cytokines synergistically increased production of CXCL8 and
beta-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of
cytokines. In vivo
intradermal injection of these five
cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine
chemokines and 12
antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this
cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of
IL-17A,
IL-22,
oncostatin M,
TNF-alpha, and IL-1alpha on keratinocytes. This is particularly interesting in the context of
psoriasis where these
cytokines are overexpressed and could synergize to play an important role in upregulation of
chemokines and
antimicrobial peptides production.