LYMPHOTOXIN-β AND TNF REGULATION IN T CELL SUBSETS: DIFFERENTIAL EFFECTS OF PGE 2

Abstract

The effects of prostaglandin E 2(PGE 2) on lymphotoxin β (LT-β) and tumour necrosis factor alpha (TNF) were assessed in murine CD4 +Th 1and Th 2T cell clones. LT-β mRNA was constitutively expressed by both T cell subsets. However, PGE 2inhibited its accumulation only in Th 1, but not Th 2clones. PGE 2inhibited TNF mRNA accumulation and production and release of bioactive material by both Th 1and Th 2T cells. The effects of PGE 2were 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 Th 2cells. Though IL-3 was produced by both T cell subsets it was only inhibited in Th 1cells, a pattern similar to that observed for LT-β. Accumulation of IL-4 mRNA in Th 2cells was not inhibited by PGE 2. These results demonstrate that PGE 2does not affect LT-β, IL-4, or IL-3 in Th 2cells, but inhibits TNF mRNA accumulation and production in this T cell subset. Thus, TNF appears to be the only cytokine susceptible to inhibition by PGE 2in Th 2cells. The fact that PGE 2inhibits LT-β and IL-3 in Th 1but not Th 2cells 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 Th 2cells, but not in Th 1cells. The inhibitory effects of PGE 2on TNF mRNA accumulation by either T cell subset did not require de novoprotein synthesis since preincubation with the protein synthesis inhibitor, cycloheximide, did not alter the PGE 2-mediated effects. Cross-regulation of cytokine production and function has been demonstrated for both T cell subsets, and PGE 2may modulate the outcome of an immune response via differential regulation of cytokine production.