Neurogenic component of phorbol ester-induced mouse skin inflammation.
Tumor-promoting phorbol esters are potent inflammatory agents for mouse skin, and the potential mechanistic role of inflammation in tumor promotion is under active investigation. We have shown previously that resiniferatoxin, a uniquely irritant phorbol-related diterpene, acts as a capsaicin analogue to induce and then to block neurogenic inflammation. We report here that pretreatment of CD-1 mice with resiniferatoxin blocked the early (3 h) erythema and edema (6 h) in response to phorbol 12-myristate 13-acetate (PMA), whereas the edema at later times (12-24 h) was only partially blocked. Since the efficiency of resiniferatoxin pretreatment decreased as a function of time if PMA was applied 24, 48, or 96 h after resiniferatoxin administration, the late edema response to PMA may be a combination of increasing edema of nonneurogenic origin and the recovering neurogenic response due to the decreasing desensitization. For other phorbol esters, 12-deoxyphorbol mono- and diesters, and mezerein, differing kinetics of edema and differing degrees of blockade of edema following resiniferatoxin pretreatment were observed, as expected from the discrepancies between their inflammatory and tumor-promoting activities. PMA-induced skin hyperplasia, unlike edema, was not inhibited by resiniferatoxin pretreatment, suggesting that the early component of neurogenic inflammation was not essential for hyperplasia under our conditions. Distinction between inflammatory mechanisms may help to clarify the role of inflammation in tumor promotion.
Szallasi
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Molecular Mechanisms of Tumor Promotion Section, National Cancer Institute, Bethesda, Maryland 20892.
Blumberg
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PM
D000287:Administration, Topical; D000818:Animals; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000139:chemically induced; D005260:Female; D006965:Hyperplasia; D007249:Inflammation; D051379:Mice; D008815:Mice, Inbred Strains; D010703:Phorbol Esters / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000294:innervation / Q000473:pathology*; D013729:Terpenes / Q000633:toxicity; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D004224:Diterpenes; D010703:Phorbol Esters; D013729:Terpenes; C011309:mezerein; C024353:resiniferatoxin; D013755:Tetradecanoylphorbol Acetate