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.