Epidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponse

Raymond L. Konger, Ethel Derr-Yellin, Jeffrey B. Travers, Jesus A. Ocana, Ravi P. Sahu

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

It is known that ultraviolet B (UVB) induces PPARγ ligand formation while loss of murine epidermal PPARγ (Pparg-/-epi) promotes UVB-induced apoptosis, inflammation, and carcinogenesis. PPARγ is known to suppress tumor necrosis factor-α (TNF-α) production. TNF-α is also known to promote UVB-induced inflammation, apoptosis, and immunosuppression. We show that Pparg-/-epi mice exhibit increased baseline TNF-α expression. Neutralizing Abs to TNF-α block the increased photo-inflammation and photo-toxicity that is observed in Pparg-/-epi mouse skin. Interestingly, the increase in UVB-induced apoptosis in Pparg-/-epi mice is not accompanied by a change in cyclobutane pyrimidine dimer clearance or in mutation burden. This suggests that loss of epidermal PPARγ does not result in a significant alteration in DNA repair capacity. However, loss of epidermal PPARγ results in marked immunosuppression using a contact hypersensitivity (CHS) model. This impaired CHS response was significantly alleviated using neutralizing TNF-α antibodies or loss of germline Tnf. In addition, the PPARγ agonist rosiglitazone reversed UVB-induced systemic immunosuppression (UVIS) as well as UV-induced growth of B16F10 melanoma tumor cells in syngeneic mice. Finally, increased B16F10 tumor growth was observed when injected subcutaneously into Pparg-/-epi mice. Thus, we provide novel evidence that epidermal PPARγ is important for cutaneous immune function and the acute photoresponse.

Original languageEnglish (US)
Pages (from-to)98184-98199
Number of pages16
JournalOncotarget
Volume8
Issue number58
DOIs
StatePublished - 2017

Keywords

  • Contact hypersensitivity
  • Immunosuppression
  • Peroxisome proliferator-activated receptor G
  • Tumor necrosis factor alpha
  • Ultraviolet

ASJC Scopus subject areas

  • Oncology

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