Biomedical subjects

C S Baxter

Publications and source records attributed to C S Baxter.

At least 37 records · Page 2Linked to original sources

PubMed1987

Mechanism of mouse skin tumor promotion by n-dodecane.

Application of the alkane n-dodecane to the dorsal skin of 6-8 week old female SENCAR mice initiated with 10 nmol dimethylbenz[a]anthracene led to papilloma formation in the majority of treated animals. Compared to the potent phorbol diester 12-O-tetradecanoylphorbol-13-acetate (TPA), n-dodecane was several orders of magnitude less potent on a dose basis, and maximal papilloma response required more extended application (22 weeks for 50 mg dodecane compared to 12 weeks for 2 micrograms TPA). In two-stage promotion experiments n-dodecane appeared to act as a stage II promoting agent at appropriate doses, being comparable in activity to mezerein--an agent with well-characterized activity of this type. Dodecane, unlike mezerein, did not induce the formation of a significant number of pyknotic cells, however, suggesting that the weak promoting activity of dodecane in stage 1 was not a result of toxicity. In comparison with TPA, both mezerein and n-dodecane at promoting doses induced less sustained hyperplasia in SENCAR mouse skin, a finding also consistent with the proposal that n-dodecane is principally active in stage II of two-stage promotion models. Both agents induced ornithine decarboxylase activity in SENCAR mouse skin, the maximal induction being observed at apparently the same time after a single application.

Acetone↗

PubMed1986

Phorbol diester synergistically stimulates agonist-induced lipoxygenase product formation in murine macrophages.

Murine peritoneal macrophages were preincubated with 12-O-tetradecanoylphorbol-13-acetate (100 ng/ml) and then exposed to various concentrations of calcium ionophore A23187. This combined treatment resulted in an elevated release of arachidonic acid metabolites that was synergistic in nature. Resolution of the [3H]products released into the medium revealed that the effect on the cyclooxygenase products 6-keto PGF1 and PGE2 were additive to less than additive (A23187 concentration dependent), the production of lipoxygenase products was synergistically enhanced, and the largest effect was on 12-HETE production.

Animals↗

PubMed1986

Decreased sulfation of cellular chondroitin sulfate in response to activators of protein kinase C.

The sulfation of cellular chondroitin sulfate in human promyelocytic leukemia HL60 cells was inhibited by a number of phorbol diesters, which concurrently induced differentiation into monocytic cells. Inhibition was dependent on concentration, and was 90% complete at 10 nM 12-0-tetradecanoylphorbol-13-acetate (TPA), the most active ester. Maximal effects were seen within 2-4 hours following initiation of treatment. The degree of inhibition observed correlated well with the ability of the esters to induce differentiation, and with their reported affinity for a "receptor", identified as protein kinase C associated with certain lipids. Chondroitin sulfation was also inhibited in cells treated with sn-1,2-dioctanoylglycerol, a lipid which is considered to be an endogenous activator of protein kinase C. Our findings therefore indicate that monocytic differentiation of HL60 cells occurs subsequent to reduced glycosaminoglycan sulfation via activation of the calcium-activated, phospholipid-dependent protein kinase.

Cell Differentiation↗

PubMed1986

Topical application of a tumor promoter induces proliferation of an adherent cell population in murine spleen.

The tumor-promoting phorbol esters have proven to be potent immunomodulatory agents in vitro. It has not been possible to assess the role of phorbol ester-induced alterations of immune function in tumor promotion however, due to a lack of in vivo studies. Studies were therefore designed to assess proliferative responses of murine leukocytes after in vivo exposure to these agents. Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was found to cause an increase in division of murine spleen cells. The effect was dose-related up to 14 micrograms per application and generally reached a peak two days after TPA application. Cell separation experiments suggested TPA was acting on an adherent cell population distinct from splenic lymphocytes. Inflammatory reactions to TPA followed a similar time-course to that observed for spleen cell proliferation. The increased levels of proliferation observed could, therefore, be due to increased division of neutrophil and/or macrophage precursors residing in the murine spleen and appeared also to be associated with the inflammatory reaction induced by TPA.

Administration, Topical↗

PubMed1985

Specific stimulation of histone H2B and H4 phosphorylation in mouse lymphocytes by 12-O-tetradecanoylphorbol 13-acetate.

This report demonstrates that the potent tumor promoter 12-O-tetradecanoylphorbol 13-acetate rapidly stimulates the phosphorylation of histones H2B and H4 in a cell cycle-independent manner. This effect was observed in primary cultures of BALB/c mouse splenocytes, a population of noncycling, G0 cells which are not stimulated to divide by 12-O-tetradecanoylphorbol 13-acetate treatment alone. The biological nature of this cell system allowed the analysis of histone phosphorylation in the absence of a background of cell cycle-dependent changes and in response to a nonmitogenic agent. The phosphorylation of H2B was determined with high resolution through the use of two-dimensional gel electrophoresis. In contrast to 12-O-tetradecanoylphorbol 13-acetate, the mitogen from pokeweed did not induce stimulation of H2B and H4 phosphorylation, but did, however, elicit increases in the phosphorylation of histones H1, H2A, and H3, in parallel with changes in rate of DNA synthesis.

Animals↗

PubMed1985

Specific stimulation by phorbol esters of the phosphorylation of histones H2B and H4 in murine lymphocytes.

The effect of phorbol diesters on histone phosphorylation in BALB/c mouse lymphocytes, cells which do not respond to these agents with cell division, but with other biochemical and biological changes, was investigated. A technique for fractionating the proteins was used which was more powerful than those used previously in similar studies of phorbol diester effects on the metabolism of these proteins. Exposure of lymphocytes to tumor-promoting phorbol esters resulted in a rapid and specific increase in phosphorylation of the nuclear histone proteins H2B and H4. Within 2 hr, the phosphorylation of these two proteins rose to levels 6- to 8- and 2- to 4-fold greater, respectively, than those in control cells, when lymphocytes were exposed to 800 nM 12-O-tetradecanoylphorbol-13-acetate. Lower levels were observed with other phorbol analogues commensurate with their relative tumor-promoting abilities. Lymphocyte mitogens did not increase phosphorylation under the conditions used. The potential ability of the cell system used for defining early in vivo and in vitro phorbol diester effects, and those which are independent of cell division, is discussed.

Animals↗

PubMed1984

Carrageenan-induced suppression of T-lymphocyte proliferation in the rat: abrogation of suppressor factor production by the prostaglandin synthesis inhibitors, indomethacin and ETYA.

Carrageenan, an algal polygalactan reputed to be selectively toxic for macrophages, is widely employed as a tool to dissect pathways of cell-mediated immunity. In the present study, corn oil-elicited rat peritoneal macrophages after 72 h culture with 10 micrograms/ml Seakem 9 Carrageenan secreted a soluble suppressor factor capable of abrogating T-cell activation by phytohemagglutinin-P (PHA). Addition of the prostaglandin synthesis inhibitors Indomethacin or 5,8,11,14-eicosatetraynoic acid (ETYA) prevented inhibitor synthesis by Carrageenan-conditioned macrophages. Seakem 9 and lambda Carrageenans added directly into spleen cell cultures failed to diminish lymphocyte proliferation, but rather stimulated spleen cell division. Macrophages cultured with low concentrations of Carrageenan appeared to be activated on the basis of enhanced tumoristatic capacity against Schmidt-Ruppin sarcoma cells. Thus, macrophages activated by low concentrations of Carrageenan in vitro appear to secrete a product of arachidonic acid metabolism which is a potent inhibitor of PHA-induced spleen cell mitogenesis.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1984

Macrophage-mediated suppression of T lymphocyte proliferation induced by oral carrageenan administration.

Carrageenan, a high molecular weight sulphated polygalactan, is a potent inhibitor of immune responses mediated by macrophages. In the present study, spleen cells from rats orally dosed with 5 mg/kg or 50 mg/kg Seakem 9 carrageenan displayed a long-lasting depression of T lymphocyte mitogenesis as measured by [3H]-thymidine uptake in response to phytohaemagglutinin (PHA) or concanavalin A (Con A). Maximal suppression of splenic T cell proliferation occurred with the low dose (5 mg/kg) of orally administered carrageenan. Removal of adherent cells restored the PHA mitogenic response, suggesting a macrophage-mediated mechanism in suppression of lymphocyte activation. Rats which received 5 mg/kg carrageenan displayed impaired host resistance to Listeria monocytogenes as evidenced by increased numbers of Listeria in the peritoneal cavity 18 hr after i.p. inoculation. Supernatants from peritoneal exudate macrophages, as well as resident macrophages themselves obtained from carrageenan-fed rats, also suppressed PHA-induced spleen cell mitogenesis. These data support the hypothesis that low doses of orally administered carrageenan stimulate a population of macrophages to actively suppress T lymphocyte proliferation, while high doses abolish suppressor activity.

Animals↗

PubMed1984