Topical application of a platelet activating factor receptor agonist suppresses phorbol ester-induced acute and chronic inflammation and has cancer chemopreventive activity in mouse skin

• Published in: PloS one 2014-11, Vol.9 (11), p.e111608
• Main Authors: Sahu, Ravi P, Rezania, Samin, Ocana, Jesus A, DaSilva-Arnold, Sonia C, Bradish, Joshua R, Richey, Justin D, Warren, Simon J, Rashid, Badri, Travers, Jeffrey B, Konger, Raymond L
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Activation; Administration, Topical; Anaphylaxis; Animals; Anti-Inflammatory Agents - administration & dosage; Antineoplastic Agents - administration & dosage; B cells; Biology and Life Sciences; Blood platelets; c-Kit protein; Cancer; Cancer prevention; Cancer treatment; Carcinogenesis; Carcinogens; Data processing; Departments; Dermatology; Disease Models, Animal; Ear; Edema; Epidermis - drug effects; Epidermis - pathology; G protein-coupled receptors; Histamine; Immunomodulation; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Kinases; Laboratories; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Pathology; Phorbol esters; Phorbol Esters - adverse effects; Platelet Membrane Glycoproteins - agonists; Platelet Membrane Glycoproteins - genetics; Platelet-activating factor; Platelets; Protein binding; Proteins; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Research and Analysis Methods; Rodents; Skin; Skin Neoplasms - chemically induced; Skin Neoplasms - drug therapy; Topical application; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0111608

Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.