IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

Gosmann, Christina; Mattarollo, Stephen R.; Bridge, Jennifer A.; Frazer, Ian H.; Blumenthal, Antje

doi:10.4049/jimmunol.1400216

Cited by 58 publications

(68 citation statements)

References 51 publications

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“…3b). Baseline levels of IL-17A in untreated K14.E7 skin were also higher than those in C57BL/6 skin, as reported previously [24]. Thus, in addition to Th2 cytokines, IL-17A was induced in K14.E7 skin in response to DNCB.…”

Section: Resultssupporting

confidence: 66%

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

Tran¹,

Mittal²,

Mattarollo³

et al. 2015

J Innate Immun

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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.

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Section: Resultssupporting

confidence: 66%

“…A recent study in our laboratory suggested that expression of HPV16.E7 oncoprotein leads to elevated production of IL-17A in the skin of K14.E7 mice and hyperplastic cervical tissue [24]. To date, there is no evidence in the literature that HPV16.E7 protein can directly affect the transcription of arginase.…”

Section: Discussionmentioning

confidence: 99%

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

Tran¹,

Mittal²,

Mattarollo³

et al. 2015

J Innate Immun

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“…Additionally, DNCB-treated K14.E7 skin secreted more IL-17A into the skin explant supernatant than wild-type skin (Figure 3.3b). Base levels of IL-17A in untreated K14.E7 skin were also higher than that in C57BL/6 skin, as reported previously (35). Thus, in addition to Th2 cytokines, IL-17A was induced in K14.E7 skin in response to DNCB.…”

Section: Il-17a Is Specifically Induced In Dncb-treated K14e7 Skin Isupporting

confidence: 86%

“…In contrast, a recent study using HPV16 E7 trangenic skin transplantation has shown that IL-17A produced by CD4 + T cells is responsible for the suppression of immune effector functions (35).…”

Section: Cd4mentioning

confidence: 91%

“…Likewise, RNAseq data (data in preparation for publication) showed the impact of E7 expression on a wide range of genes but not on Arginase-1 or 2. A recent study in our laboratory suggested that expression of the HPV16.E7 oncoprotein leads to the elevated production of IL-17A in the skin of K14.E7 mice and hyperplastic cervical tissue (35).…”

Section: The Involvement Of Hpv16e7 Protein In Il-17a and Arginase Imentioning

confidence: 95%

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Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Tran¹

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Persistent infection with oncogenic human papillomaviruses (HPV), particularly HPV16, is associated with selective expression of two virally encoded proteins (E6 and E7). One action of HPV16.E7 protein is to subvert the innate immune system through the down-regulation of IFNγ pathways, modulation of antigen presentation, and suppression of Toll-like receptor 9 protein.K14.E7 transgenic mice, which express HPV16.E7 oncoprotein within basal keratinocytes under the control of the keratin 14 transcriptional promoter, have been extensively used as a model of HPV oncoprotein-induced immune suppression associated with human squamous cancers, in which only the E6 and E7 genes of the papillomavirus are expressed. It has previously been shown that skin grafts expressing HPV16.E7 oncoprotein are not spontaneously rejected when transplanted onto syngeneic animals, but they are rejected when certain components of the innate immune system are unavailable, confirming that the expression of HPV16.E7 in the epithelium results in the establishment of a local suppressive environment and the subversion of antigen-specific T cells. Therefore, successful strategies targeting HPV-associated cancer need to circumvent or disrupt the local suppressive environment.Topical immunotherapy with immunostimulatory agents has been used clinically to treat cancerous lesions including squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. Topical application of 2,4-dinitrochlorobenzene (DNCB) is an effective therapy for condylomata acuminata caused by HPV infection. DNCB induced the complete clearance of HPV-associated warts in 13/15 patients. However, the use of DNCB for treatment has been discouraged because of its mutagenic potential. The aim of my doctoral research is to understand the mechanism of DNCB-induced inflammation in K14.E7 transgenic mice which has been poorly understood. I hypothesized that understanding how induction of a vigorous acute inflammatory response by DNCB can break the local immune-suppressive environment and restore the effector function of adaptive immunity might lead to more acceptable treatments for persisting HPV infection. In support of this hypothesis, the present study showed that DNCB application along with E7 specific immunization therapy was capable of inducing HPV16.E7 skin graft rejection.Arginase, which metabolizes l-arginine to N-ornithine and urea, has been identified as a crucial regulator of inflammation. As inflammation decides the fate of HPV infection and arginase is an important regulator of inflammation and immunity, I investigated the ii interaction between DNCB-induced inflammation and HPV16.E7 protein in the induction of arginase in K14.E7 transgenic mice. The first part of this study showed 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 Taken together, my study suggests that HPV16.E7 protein enhances DNCB associated-prod...

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Occurrence of Extensive Cutaneous Human Papillomavirus Infection After Initiation of Tofacitinib Therapy

et al. 2019

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IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

Cited by 58 publications

References 51 publications

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

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

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Occurrence of Extensive Cutaneous Human Papillomavirus Infection After Initiation of Tofacitinib Therapy

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