Immunoinflammatory response to 12-O-tetradecanoylphorbol-13-acetate (TPA) in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice: The significance for tumor promotion

Lawrence William Updyke, Purdue University

Abstract

Multiple hypotheses have been advanced for a common mechanism by which all tumor promoters act. These studies investigate the effects of tumor promoters on cell-cell communication, immune and natural resistance functions and release of inflammatory mediators. Intercellular junctional communication among mutant human fibroblasts was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA), but not by benzoyl peroxide (BZP). Alternatively, in vitro incubation with BZP decreased splenic cell responsiveness to phytohemagglutinin (PHA), a T cell mitogen. Topical application of TPA caused a potent dermal inflammatory response, 2-3 fold and 10-20 fold increases in splenic and superficial inguinal lymph node cell numbers, respectively, in TPA-sensitive SENCAR mice. TPA-resistant B6C3F1 mice exposed to identical dosing regimens demonstrate a much less potent inflammatory response, no increase in splenic cell number and a 4-7 fold increase in lymph node cell number. Concomitantly, in both strains a significant increase in nodal cell and decrease in splenic cell responsiveness to PHA were observed. Importantly, splenic and nodal NK activity was increased in B6C3F1 mice while splenic NK activity was reduced in TPA-sensitive SENCAR mice. Application of BZP caused a less potent inflammatory response and no changes in splenic cell number in both strains. A 5-6 fold and 10-fold increase in nodal cell numbers were noted in BZP-resistant B6C3F1 and BZP-sensitive SENCAR mice, respectively. Similar to findings after exposure to TPA, there is a significant increase in splenic NK activity in B6C3F1 mice; no changes were noted in SENCAR NK activity. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) can stimulate NK activity. Topical application of TPA primed splenic MPs from both B6C3F1 and SENCAR mice for lipopolysaccharide-triggered release of these cytokines. MP-dependent suppression of NK activity following in vitro exposure to 1.0 uM TPA indicated the potential importance of MP regulation of NK activity during tumor promotion. SENCAR mice demonstrated significantly greater increases in serum granulocyte-macrophage colony-stimulating factor (GM-CSF) following topical application of TPA than did B6C3F1 mice. Taken together these data suggest that in SENCAR mice the more potent release of GM-CSF following application of TPA triggers MP-mediated suppression of NK activity, thus reducing the body's defense against tumor development. Alternatively, in B6C3F1 mice increased IL-1 and TNF release in the absence of potent GM-CSF release causes a stimulation of NK activity and increased protection against tumor development.

Degree

Ph.D.

Advisors

Pfeifer, Purdue University.

Subject Area

Pharmacology|Immunology

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