Induction of suppressor macrophages by 12-O-tetradecanoylphorbol-13-acetate in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice
Abstract
Previous findings in this laboratory indicate that two-week topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) at doses relevant to two-stage chemically-induced skin carcinogenesis, i.e., 2, 4, and 8 $\mu$g/mouse, suppressed phytohemagglutinin (PHA)-induced splenic lymphocyte blastogenesis in both phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice. Furthermore, TPA decreased splenic natural killer (NK) activity in SENCAR mice but enhanced this function in B6C3F1 mice. These differential changes in NK activity may, in part, account for the reported strain-dependent differences in susceptibility to TPA-induced tumor promotion. The purposes of this study were to determine if TPA-induced suppression of splenic PHA response in both strains and the decrease in NK activity in SENCAR spleens are mediated by suppressor macrophages (MPs). Moreover, this study also determined if differential changes in MP-mediated tumor cell cytostasis as a result of TPA application might contribute to reported strain-dependent differences in sensitivity to TPA-induced tumor promotion. Similar to previous findings, topical application of TPA at 8 $\mu$g/mouse twice in one week suppressed PHA-induced splenic lymphoproliferation in both strains. This suppression was mediated by MPs and possibly non-adherent suppressor T cells. Alternatively, the decreased splenic NK activity in TPA-dosed SENCAR mice was not mediated by suppressor cells but was likely due to a decreased proportion of cells with NK activity due to the proliferation of non-NK cells. Although TPA did not alter antitumoral cytostatic activity of splenic MPs from either strain, it primed MPs for lipopolysaccharide (LPS)-triggered stimulation of cytostatic activity in B6C3F1 mice but not in SENCAR mice. Regardless of the differential MP-priming effect of TPA, the percent cytostasis mediated by MPs from TPA-treated mice of both strains were comparable. Therefore, TPA-stimulated increases in MP-mediated tumor cytostasis triggered by LPS were not correlated with the resistance of particular mouse strains to TPA-induced tumor promotion.
Degree
Ph.D.
Advisors
Pfeifer, Purdue University.
Subject Area
Pharmacology
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