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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.

Abstract
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.
AuthorsRavi P Sahu, Samin Rezania, Jesus A Ocana, Sonia C DaSilva-Arnold, Joshua R Bradish, Justin D Richey, Simon J Warren, Badri Rashid, Jeffrey B Travers, Raymond L Konger
JournalPloS one (PLoS One) Vol. 9 Issue 11 Pg. e111608 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID25375862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Phorbol Esters
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • 9,10-Dimethyl-1,2-benzanthracene
  • Proto-Oncogene Proteins c-kit
Topics
  • 9,10-Dimethyl-1,2-benzanthracene
  • Administration, Topical
  • Animals
  • Anti-Inflammatory Agents (administration & dosage)
  • Antineoplastic Agents (administration & dosage)
  • Disease Models, Animal
  • Ear
  • Epidermis (drug effects, pathology)
  • Inflammation (chemically induced, drug therapy)
  • Mice
  • Mice, Inbred C57BL
  • Phorbol Esters (adverse effects)
  • Platelet Membrane Glycoproteins (agonists, genetics)
  • Proto-Oncogene Proteins c-kit (genetics, metabolism)
  • Receptors, G-Protein-Coupled (agonists, genetics)
  • Skin Neoplasms (chemically induced, drug therapy)

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