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PAF receptor deficiency results in increased PMA‐induced inflammation and augmented chemical carcinogenesis
Author(s) -
Konger Raymond Lloyd,
Kozman Amal,
Sahu Ravi P,
Travers Jeffrey B
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.421.8
Subject(s) - inflammation , carcinogenesis , mediator , platelet activating factor , cytokine , chemistry , proinflammatory cytokine , oxidative stress , chemokine , myeloperoxidase , dmba , immunology , endocrinology , medicine , cancer research , cancer , biology , biochemistry
Platelet activating factor (PAF) is a well known proinflammatory mediator. Previous studies have shown that PAF‐like ligands are formed by various oxidative stressors. Given that phorbol esters are potent inducers of both inflammation and oxidative stress, we sought to determine whether PAF acts as a mediator of topical phorbol ester–induced inflammation and subsequent neoplastic development. First, topical phorbol myristate acetate (PMA) induced the production of PAFR ligand in mouse skin. Next, relative to controls, mice lacking the PAFR (KO mice) exhibit an increase in chronic PMA application‐induced inflammation. This was seen as increased skin thickness, myeloperoxidase expression, and increased inflammatory cytokine/chemokine expression. Next, using a DMBA/PMA carcinogenesis protocol, we show that KO mice exhibit a two‐fold increase in tumor multiplicity along with an increase in squamous cell carcinomas (SCC) relative to benign papillomas (< 1% SCC in wildtype vs 32% SCCs in KO mice). The above data suggests that the PAF‐R may play a paradoxical role in suppressing inflammation associated with chronic PMA application, thus indicating a possible paradigm shift in our understanding of the role of PAF in regulating inflammation. Moreover, PAF may play an important protective role in cutaneous neoplastic development. Supported by the National Institutes of Health and the Prevent Cancer Foundation.