title: IRF6 Regulates the Expression of IL-36γ by Human Oral Epithelial Cells in Response to Porphyromonas gingivalis.
abstract: IFN regulatory factors (IRFs) help to shape the immune response to pathogens by imparting signaling specificity to individual TLRs. We recently demonstrated that IRF6 provides specificity to TLR2 signaling in oral epithelial cells. TLR2 plays an important role in eliciting inflammation to Porphyromonas gingivalis, a keystone pathogen in periodontitis. Therefore, we investigated a role for IRF6 in mediating the inflammatory cytokine response of oral epithelial cells to P. gingivalis. IRF6 expression was strongly upregulated when human oral epithelial cells were challenged with P. gingivalis. Moreover, gene silencing and gene promoter experiments indicated that IRF6 acts downstream of IL-1R-associated kinase 1 to stimulate the expression of the IL-1 family cytokine IL-36γ in response to P. gingivalis. IRF6 and IL-1R-associated kinase 1 also regulated the stimulation of IL-36γ expression by a TLR2 agonist. IL-36γ was shown to elicit inflammatory responses by human monocyte-derived dendritic cells and macrophages, including the expression of the neutrophil chemokines IL-8 and CXCL1, as well as the Th17 chemokine CCL20. IL-36γ similarly stimulated their expression by human oral epithelial cells. Significantly, the Th17 cytokine IL-17 not only stimulated the expression of important regulators of neutrophil recruitment and survival by oral epithelial cells, but IL-17 also stimulated them to express IL-36γ. Thus, our findings suggest that IRF6 is likely to promote inflammation to P. gingivalis through its regulation of IL-36γ.
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huynh
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia; and.
authors.forename: Glen M
authors.identifier: http://orcid.org/0000-0003-2722-6344
authors.initials: GM
authors.lastname: Scholz
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia; and.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Aw
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia; and Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Mei Qi
authors.initials: MQ
authors.lastname: Kwa
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Adrian
authors.identifier: http://orcid.org/0000-0003-3640-2338
authors.initials: A
authors.lastname: Achuthan
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: John A
authors.identifier: http://orcid.org/0000-0002-9493-9224
authors.initials: JA
authors.lastname: Hamilton
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia; and e.reynolds@unimelb.edu.au.
authors.forename: Eric C
authors.identifier: http://orcid.org/0000-0002-6618-4856
authors.initials: EC
authors.lastname: Reynolds
mesh_terms: D016866:Bacteroidaceae Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008954:Models, Biological; D009061:Mouth Mucosa / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D016966:Porphyromonas gingivalis / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C508589:IL36G protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D007375:Interleukin-1; D020381:Interleukin-17; D051195:Toll-Like Receptor 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases