Human papillomavirus E7 oncoprotein transgenic skin develops an enhanced inflammatory response to 2,4-dinitrochlorobenzene by an arginase-1-dependent mechanism

Le Son Tran, Anne Sophie Bergot, Stephen R. Mattarollo, Deepak Mittal, Ian H. Frazer

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2438-2446
Number of pages9
JournalJournal of Investigative Dermatology
Volume134
Issue number9
DOIs
Publication statusPublished - Sep 2014
Externally publishedYes

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