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

// Raymond L. Konger 1, 2 , Ethel Derr-Yellin 1 , Jeffrey B. Travers 2, 3 , Jesus A. Ocana 2 and Ravi P. Sahu 3 1 Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA 3 Department of Pharmacology & Toxicology, Wright State University, Dayton, OH, USA Correspondence to: Raymond L. Konger, email: rkonger@iupui.edu Keywords: contact hypersensitivity; immunosuppression; peroxisome proliferator-activated receptor Γ; ultraviolet; tumor necrosis factor alpha Received: June 14, 2017 Accepted: August 26, 2017 Published: September 18, 2017 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 (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.