title: Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease.
abstract: The IFN-γ-inducible chemokines CXCL9, CXCL10, and CXCL11 play a key role in many inflammatory conditions, particularly those mediated by T cells. Therefore, the production of these chemokines in peripheral tissues could be instrumental in the pathophysiology of tissue-specific immunological diseases such as oral lichen planus (OLP). In the present study, we assessed the production of keratinocyte-derived CXCL9/10/11 under basal and inflammatory conditions and investigated whether these chemokines were involved in the pathogenesis of OLP. We used semi-quantitative PCR, ELISA, chemotaxis assays, and fluorescence-activated cell sorting (FACS) to assess the expression and functional role of CXCL9/10/11 in oral keratinocytes (three strains of normal human oral keratinocytes (NHOK), and the H357 oral cancer cell line) in the presence or absence of IFN-γ. CXCL9/10/11 were also assessed in tissues from normal patients and those with oral lichen planus (OLP). The time course study in oral keratinocytes treated with IFN-γ showed that expression of CXCL9/10/11 chemokines was significantly enhanced by IFN-γ in a time-dependent manner. In particular, CXCL10, a prominent chemokine that was overexpressed by IFN-γ-stimulated NHOK, was able to effectively recruit CD4 lymphocytes, mainly CD4+CD45RA- cells. Significantly higher levels of CXCL9/10/11 were found in tissues from patients with OLP compared to normal oral mucosa. Taken together, the results demonstrate that normal oral keratinocytes produce chemotactic molecules that mediate T cell recruitment. This study furthers understanding of chemokine production in oral keratinocytes and their role in the pathophysiology of oral mucosa, with particular relevance to OLP.
authors.affiliation: University College London, UCL Eastman Dental Institute, London, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.|Melbourne Dental School and Oral Health CRC, The University of Melbourne, Victoria, Australia.
authors.forename: Antonio
authors.initials: A
authors.lastname: Celentano
authors.affiliation: Melbourne Dental School and Oral Health CRC, The University of Melbourne, Victoria, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cirillo
authors.affiliation: Melbourne Dental School and Oral Health CRC, The University of Melbourne, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: McCullough
authors.affiliation: University College London, UCL Eastman Dental Institute, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Porter
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017676:Lichen Planus, Oral / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D009061:Mouth Mucosa / Q000473:pathology; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D007371:Interferon-gamma