title: Human papillomavirus e7 oncoprotein transgenic skin develops an enhanced inflammatory response to 2,4-dinitrochlorobenzene by an arginase-1-dependent mechanism.
abstract: We have shown that the expression of human papillomavirus type 16 E7 (HPV16.E7) protein within epithelial cells results in local immune suppression and a weak and ineffective immune response to E7 similar to that occuring in HPV-associated premalignancy and cancers. However, a robust acute inflammatory stimulus can overcome this to enable immune elimination of HPV16.E7-transformed epithelial cells. 2,4-Dinitrochlorobenzene (DNCB) can elicit acute inflammation and it has been shown to initiate the regression of HPV-associated genital warts. Although the clinical use of DNCB is discouraged owing to its mutagenic potential, understanding how DNCB-induced acute inflammation alters local HPV16.E7-mediated immune suppression might lead to better treatments. Here, we show that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, which is not seen in nontransgenic control animals. The E7-associated inflammatory response is characterized by enhanced expression of Th2 cytokines and increased infiltration of CD11b(+)Gr1(int)F4/80(+)Ly6C(hi)Ly6G(low) myeloid cells, producing arginase-1. Inhibition of arginase with an arginase-specific inhibitor, N(omega)-hydroxy-nor-L-arginine, ameliorates the DNCB-induced inflammatory response. Our results demonstrate that HPV16.E7 protein enhances DNCB-associated production of arginase-1 by myeloid cells and consequent inflammatory cellular infiltration of skin.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: L S
authors.initials: LS
authors.lastname: Tran
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: A-S
authors.initials: AS
authors.lastname: Bergot
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: S R
authors.initials: SR
authors.lastname: Mattarollo
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Mittal
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: I H
authors.initials: IH
authors.lastname: Frazer
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D004139:Dinitrofluorobenzene / Q000633:toxicity*; D003875:Drug Eruptions / Q000276:immunology* / Q000473:pathology; D004431:Ear, External / Q000276:immunology / Q000473:pathology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000276:immunology* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D004139:Dinitrofluorobenzene; C544448:Arg1 protein, mouse; D001119:Arginase
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