title: Differential activation and inhibition of lymphocyte proliferation by phorbol esters, mezerein, teleocidin, and okadaic acid.
abstract: Lymphocytes can be stimulated to proliferate in vitro by mitogens such as concanavalin A. The tumor-promoting phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) can enhance this proliferation, partly because of an increase in interleukin 2 (IL-2) production. However, if lymphocytes are treated with TPA for 24 h before concanavalin A exposure, IL-2 production and proliferation are depressed. The target of the action of TPA is protein kinase C, which is activated after a short exposure but down-regulated after a longer one. This study was designed to determine if the modulation of IL-2 was separable from the modulation of protein kinase C. When phorbol esters phorbol 12-retinoate-13-acetate, phorbol 12,13-dibutyrate, 12-deoxyphorbol 13-phenylacetate, and 12-deoxyphorbol 13-phenylacetate-20-acetate, as well as nonphorbol tumor promoters mezerein, telocidin, and okadaic acid, were tested, all but okadaic acid reproduced the effects of TPA. However, 12-deoxyphorbol 13-phenylacetate and 12-deoxyphorbol 13-phenylacetate-20-acetate were required at nearly 100-fold higher concentrations than TPA to suppress IL-2 production, suppress mitogenesis, and cause down-regulation of protein kinase C. A comparison of structures indicated that an R group at the 12-position was less important for IL-2 production and mitogenesis than for down-regulation of protein kinase C and the suppression of mitogenesis. In no case was the modulation of protein kinase C separated from the effects on IL-2 production and proliferation.
authors.affiliation: Department of Molecular and Cell Biology, Pennsylvania State University, University Park 16802.
authors.forename: D S
authors.initials: DS
authors.lastname: Grove
authors.forename: A M
authors.initials: AM
authors.lastname: Mastro
mesh_terms: D000818:Animals; D002417:Cattle; D002451:Cell Compartmentation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004988:Ethers, Cyclic / Q000494:pharmacology*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects*; D008235:Lyngbya Toxins / Q000494:pharmacology*; D019319:Okadaic Acid; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D004224:Diterpenes; D004988:Ethers, Cyclic; D007376:Interleukin-2; D008235:Lyngbya Toxins; D010703:Phorbol Esters; D013729:Terpenes; D003208:Concanavalin A; D019319:Okadaic Acid; C022176:teleocidins; C011309:mezerein; D011493:Protein Kinase C