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

Konger, Raymond L.Derr-Yellin, EthelTravers, Jeffrey B.Ocana, Jesus A.Sahu, Ravi P.2018-08-032018-08-032017-09-18Konger, R. L., Derr-Yellin, E., Travers, J. B., Ocana, J. A., & Sahu, R. P. (2017). Epidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponse. Oncotarget, 8(58), 98184–98199. https://doi.org/10.18632/oncotarget.210021949-2553https://hdl.handle.net/1805/16971It 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 (UV-IS) 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.en-USAttribution 3.0 United Statescontact hypersensitivityimmunosuppressionperoxisome proliferator-activated receptor Γtumor necrosis factor alphaultravioletEpidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponseArticle