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

Ravi P. Sahu, Samin Rezania, Jesus A. Ocana, Sonia C. DaSilva-Arnold, Joshua R. Bradish, Justin D. Richey, Simon Warren, Badri Rashid, Jeffrey Travers, Raymond Konger

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article numbere111608
JournalPLoS One
Volume9
Issue number11
DOIs
StatePublished - Nov 6 2014

Fingerprint

platelet-activating factor
Platelet Activating Factor
topical application
Phorbol Esters
agonists
Skin
inflammation
esters
Inflammation
receptors
neoplasms
mice
Neoplasms
carcinogenesis
Carcinogenesis
Chemical activation
edema
ears
Edema
platelet activating factor receptor

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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. / Sahu, Ravi P.; Rezania, Samin; Ocana, Jesus A.; DaSilva-Arnold, Sonia C.; Bradish, Joshua R.; Richey, Justin D.; Warren, Simon; Rashid, Badri; Travers, Jeffrey; Konger, Raymond.

In: PLoS One, Vol. 9, No. 11, e111608, 06.11.2014.

Research output: Contribution to journalArticle

Sahu, Ravi P. ; Rezania, Samin ; Ocana, Jesus A. ; DaSilva-Arnold, Sonia C. ; Bradish, Joshua R. ; Richey, Justin D. ; Warren, Simon ; Rashid, Badri ; Travers, Jeffrey ; Konger, Raymond. / 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. In: PLoS One. 2014 ; Vol. 9, No. 11.
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