title: RIPK4 activates an IRF6-mediated proinflammatory cytokine response in keratinocytes.
abstract: Keratinocytes of the oral mucosa and epidermis play key roles in host defense. In addition to functioning as a physical barrier, they also produce cytokines to elicit inflammation in response to infection or injury. We recently established that receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) function as a cell-intrinsic signaling axis to regulate keratinocyte differentiation. In this study, we have demonstrated a functional relationship between RIPK4 and IRF6 in the control of proinflammatory cytokine expression in keratinocytes. The overexpression of RIPK4 by oral keratinocytes induced the strong expression of CCL5 and CXCL11. In contrast, the expression of other cytokines (e.g. IL8 and TNF) was largely unaffected, thus demonstrating specificity in the induction of proinflammatory cytokine expression by RIPK4. CCL5 and CXCL11 expression were also induced in response to the activation of the PKC pathway, and gene silencing experiments indicated that their inducible expression was dependent on RIPK4 and IRF6. Moreover, gene reporter assays suggested that RIPK4 induces CCL5 and CXCL11 expression by stimulating the transactivation of their promoters by IRF6. Accordingly, our findings suggest that the RIPK4-IRF6 signaling axis plays a multifaceted role in barrier epithelial homeostasis through its regulation of both keratinocyte inflammation and differentiation.
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Mei Qi
authors.initials: MQ
authors.lastname: Kwa
authors.affiliation: Oral Health Cooperative Research Centre, Melbourne Dental School, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Glen M
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. Electronic address: e.reynolds@unimelb.edu.au.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Reynolds
mesh_terms: D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D054371:Chemokine CXCL11 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C483024:CCL5 protein, human; C515202:CXCL11 protein, human; D018946:Chemokine CCL5; D054371:Chemokine CXCL11; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: CCL5; CXCL11; IRF6; Keratinocyte; RIPK4