Interleukin-6-type cytokines upregulate expression of multidrug resistance-associated proteins in NHEK and dermal fibroblasts

Normal human epidermal keratinocytes (NHEK) and dermal fibroblasts express a cell-specific pattern of efflux transport proteins. Since regulatory mechanisms for these transporters in cells of the human skin were unknown, we analyzed the influence of inflammatory cytokines on the expression of multidrug resistance-associated proteins (MRP1, 3, 4, 5). Using real-time PCR, RT-PCR, cDNA microarray, immunostaining and efflux assays we demonstrated that stimulation of NHEK and primary human dermal fibroblasts with interleukin-6 (IL-6), in combination with its soluble alpha-receptor, or oncostatin M (OSM) for 24-72 h resulted in an upregulation of MRP expression and activity. Both cytokines induced a strong activation of signal transducer and activator of transcription (STAT)1 and STAT3 as well as the mitogen-activated protein kinase (MAPK) Erk1/2. OSM additionally activated proteinkinase B strongly. Using the MAPK/extracellular signal-regulated kinase kinase 1-specific inhibitor U0126 we could exclude a stimulatory effect of MAPK on MRP gene expression. Inhibition of the phosphatidylinositol 3-kinase, however, indicated that this pathway might be involved of OSM-mediated upregulation of MRP4 in dermal fibroblasts. Several inflammatory skin diseases show an enhanced expression of IL-6-type cytokines. Correspondingly, upregulation of MRP expression was found in lesional skin taken from patients with psoriasis and lichen planus.