title: Hypoxic modulation of hepatocyte responses to the cytokine interleukin-22.
abstract: The cytokine interleukin-22 (IL-22) is a potent regulator of tissue responses during inflammation. Depending on the context of inflammation, IL-22 can have protective or inflammatory effects on epithelial cells. This dual nature of IL-22 leads us to hypothesize that its activity must be exquisitely regulated to prevent host tissue damage. Environmental factors may act as a cellular cue as to how cells respond to IL-22. Inflammatory environments are characterized by low oxygen and thus we examined whether cells respond differently to IL-22 hypoxia compared with normoxia. In this study, we show that hepatocyte responses to IL-22 stimulation are reduced in hypoxic environments. IL-22 stimulation of hepatocytes incubated in low oxygen led to reduced levels of activated signal transducer and activator of transcription 3 and further downstream effects such as reduced induction of the anti-microbial protein, lipocalin-2. This modulation appears to be independent of the hypoxia-inducible factor-1α signaling pathway. Thus, hypoxia that accompanies chronic inflammation may be a mechanism to regulate the bioactivity of the dual-natured IL-22 cytokine.
authors: Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors: Scott A
authors: SA
authors: Budda
authors: Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors: Krishna
authors: K
authors: Bhattarai
authors: Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors: Justine L
authors: JL
authors: Alexander
authors: Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
authors: Lauren A
authors: LA
authors: Zenewicz
mesh_terms: D000818:Animals; D002460:Cell Line; D060833:Cellular Microenvironment; D019610:Cytoprotection; D015536:Down-Regulation; D004847:Epithelial Cells / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology*; D000860:Hypoxia / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism*; D000071068:Lipocalin-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007378:Interleukins; D000071068:Lipocalin-2; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C497443:Hif1a protein, mouse; C494087:Stat3 protein, mouse