title: Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2-IL-36γ Pathway.
abstract: The Nrf2 transcription factor is well known for its cytoprotective functions through regulation of genes involved in the detoxification of reactive oxygen species or toxic compounds. Therefore, activation of Nrf2 is a promising strategy for the protection of tissues from various types of insults and for cancer prevention. However, recent studies revealed a proinflammatory activity of activated Nrf2 and a stimulating effect on epithelial cell proliferation, but the underlying mechanisms of action and the responsible target genes are largely unknown. Using a combination of gene expression profiling, chromatin immunoprecipitation, and targeted proteomics via selected reaction monitoring, we show that the gene encoding the proinflammatory cytokine IL-36γ is a novel direct target of Nrf2 in keratinocytes and hepatocytes in vitro and in vivo. As a consequence, upregulation of IL-36γ expression occurred upon genetic or pharmacological activation of Nrf2 in the epidermis and in the normal and regenerating liver. Functional in vitro studies demonstrate that IL-36γ directly stimulates proliferation of keratinocytes. In particular, it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the Nrf2-IL-36γ axis promotes keratinocyte proliferation through a double paracrine loop. These results provide mechanistic insight into Nrf2 action in the control of inflammation and cell proliferation through regulation of a proinflammatory cytokine with a key function in various inflammatory diseases.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Kurinna
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and.
authors.forename: Sukalp
authors.initials: S
authors.lastname: Muzumdar
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and.
authors.forename: Ulrike Anne
authors.initials: UA
authors.lastname: Köhler
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and Functional Genomics Center Zurich, Swiss Federal Institute of Technology (ETH) Zurich/University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kockmann
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Auf dem Keller
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and sabine.werner@biol.ethz.ch matthias.schaefer@biol.ethz.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; and sabine.werner@biol.ethz.ch matthias.schaefer@biol.ethz.ch.
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019899:Paracrine Communication
chemical_list: C569167:IL1F9 protein, mouse; D007375:Interleukin-1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse