title: Lymphotoxin-beta and TNF regulation in T cell subsets: differential effects of PGE2.
abstract: The effects of prostaglandin E2 (PGE2) on lymphotoxin beta (LT-beta) and tumour necrosis factor alpha (TNF) were assessed in murine CD4+ Th1 and Th2 T cell clones. LT-beta mRNA was constitutively expressed by both T cell subsets. However, PGE2 inhibited its accumulation only in Th1, but not Th2 clones. PGE2 inhibited TNF mRNA accumulation and production and release of bioactive material by both Th1 and Th2 T cells. The effects of PGE2 were also evaluated on production of IL-3, another cytokine produced by both T cell subsets, and interleukin 4 (IL-4), which is produced only by Th2 cells. Though IL-3 was produced by both T cell subsets it was only inhibited in Th1 cells, a pattern similar to that observed for LT-beta. Accumulation of IL-4 mRNA in Th2 cells was not inhibited by PGE2. These results demonstrate that PGE2 does not affect LT-beta, IL-4, or IL-3 in Th2 cells, but inhibits TNF mRNA accumulation and production in this T cell subset. Thus, TNF appears to be the only cytokine susceptible to inhibition by PGE2 in Th2 cells. The fact that PGE2 inhibits LT-beta and IL-3 in Th1 but not Th2 cells points to a different mechanism of regulation of the same cytokine in different subsets. The mechanisms that contribute to TNF mRNA accumulation also may differ in the two CD4+ T cell subsets, because cycloheximide superinduced TNF mRNA in Th2 cells, but not in Th1 cells. The inhibitory effects of PGE2 on TNF mRNA accumulation by either T cell subset did not require de novo protein synthesis since preincubation with the protein synthesis inhibitor, cycloheximide, did not alter the PGE2-mediated effects. Cross-regulation of cytokine production and function has been demonstrated for both T cell subsets, and PGE2 may modulate the outcome of an immune response via differential regulation of cytokine production.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Ferreri
authors.forename: I
authors.initials: I
authors.lastname: Millet
authors.forename: B
authors.initials: B
authors.lastname: Askari
authors.forename: P
authors.initials: P
authors.lastname: Magnani
authors.forename: N H
authors.initials: NH
authors.lastname: Ruddle
mesh_terms: D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D007377:Interleukin-3 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053308:Lymphotoxin-beta; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D010120:Oxytocics / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016176:T-Lymphocyte Subsets; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D007377:Interleukin-3; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D010120:Oxytocics; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D003513:Cycloheximide; D015232:Dinoprostone