Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin

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

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5 Citations (Scopus)

Abstract

Human papillomaviruses (HPVs) have evoked numerous mechanisms to subvert host innate immunity and establish a local immunosuppressive environment to facilitate persistent virus infection. Topical application of 2,4-dinitrochlorobenzene (DNCB) was speculated to overcome this immunosuppressive environment and was employed in the immunotherapy of HPV-associated lesions. We have previously shown that DNCB treatment of skin expressing HPV16.E7 protein, the major oncogenic protein expressed in HPV-associated premalignant cervical epithelium, results in a hyperinflammatory response, with an associated induction of Th2 cytokines and infiltration of myeloid cells producing arginase-1, which also contributes to the hyperinflammation. However, the molecular mechanisms underlying arginase-1 induction and arginase-mediated hyperinflammation in K14.E7 skin have not been elucidated. Here, we show that HPV16.E7 protein expression as a transgene in skin is associated with enhanced IL-17A production by macrophages exposed to DNCB. Interestingly, induction of arginase-1 by DNCB is not seen in K14.E7 animals unable to express IL-17A. Further, blockade of either IL-17A or arginase activity alleviates DNCB-induced hyperinflammation through reduced recruitment of neutrophils, as a consequence of decreased CXCL1 and CXCL5 chemokine production. Thus, our findings suggest that increased IL-17A expression by macrophages in E7-expressing skin exposed to DNCB promotes arginase-1 induction and contributes directly to the observed hyperinflammation.

Original languageEnglish
Pages (from-to)392-404
Number of pages13
JournalJournal of Innate Immunity
Volume7
Issue number4
DOIs
Publication statusPublished - 22 Jul 2015
Externally publishedYes

Keywords

  • 2 4-Dinitrochlorobenzene
  • Bone marrow-derived macrophages
  • Human papillomavirus
  • IL-17A
  • mRNA
  • N-hydroxy-nor-L-arginine

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