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.
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.
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Ravi P
RP
Sahu
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Samin
S
Rezania
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Jesus A
JA
Ocana
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America; Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Sonia C
SC
DaSilva-Arnold
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Joshua R
JR
Bradish
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Justin D
JD
Richey
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Simon J
SJ
Warren
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Badri
B
Rashid
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America; Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, 46202, United States of America.
Jeffrey B
JB
Travers
Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America; Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.
Raymond L
RL
Konger
D015127:9,10-Dimethyl-1,2-benzanthracene; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004423:Ear; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010703:Phorbol Esters / Q000009:adverse effects; D010980:Platelet Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy*
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D010703:Phorbol Esters; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D015127:9,10-Dimethyl-1,2-benzanthracene; D019009:Proto-Oncogene Proteins c-kit