The interaction of IL-22 and TNF-α is mediated through the IL-22R heterodimer and tumor necrosis factor receptor I 26 and intracellularly by MAP kinases, in particular p38, which leads to downstream activation of AP-1 family transcription factors. The combination of IL-22 and TNF-α strongly induced the phosphorylation and translocation of MAP kinases to the nucleus whereas the single cytokines only weakly contributed to MAP kinase activation. It is known that both IL-22 27 and TNF-α 28 activate MAP kinases; however, main signaling pathways for IL-22 are mediated through the transcription factor STAT-3 and other STAT molecules 6, 24, while TNF-α strongly

induces the NF-κB signaling cascade in keratinocytes 29. Since NF-κB is not synergistically activated by the combination of

INCB024360 molecular weight TNF-α and IL-22, the observed synergism does not cover the whole functional spectra of TNF-α and IL-22, learn more but is rather limited to aspects such as innate immunity. This may explain functional diversity of TNF-α and IL-22 as well as a dual role for IL-22: alone it has protective effects and enhances wound healing 30, in combination with TNF-α it becomes immune-stimulatory and arms epithelia for innate responses. The stimulation of the epithelial immune system by the IL-22/TNF-α axis is important for defense against extracellular pathogens like C. albicans. Supernatant of keratinocytes pre-incubated with the combination of both cytokines or Th22 clone supernatant most effectively reduced Carnitine palmitoyltransferase II C. albicans growth, protected keratinocytes from apoptosis and conserved the epidermal structure in an in vitro Candida infection model. Interestingly, common side effects of an anti-TNF-α therapy (Infliximab) are serious respiratory and skin infections 31, which could be explained by the missing interaction of IL-22 with TNF-α. Therefore, the IL-22/TNF-α axis itself is protective and important for the homeostasis of the human organism and its environment; if not tightly

regulated, however, this strong synergism might turn pathologic and cause severe and chronic inflammatory skin diseases like psoriasis. In summary, the discovery of the IL-22/TNF-α axis as an essential combinatorial key for cutaneous immunity gives a first insight into the function of Th22 cells and could lead to new therapeutic approaches of chronic inflammatory skin diseases like atopic eczema and psoriasis. Primary human keratinocytes were obtained from human foreskin (Western blot analysis) or healthy adult volunteers (n=10). Before samples were taken, each participant gave his informed consent. The study was approved by the ethical committee of the Technical University Munich and was conducted according to the declaration of Helsinki. Keratinocytes were isolated using the method of suction blister as described previously 32. Briefly, blisters were induced by generating a vacuum on normal skin of the forearms. Epidermal sheets were obtained from blister roofs, treated with 0.