IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA.
We characterized the effects of rIL-1 and rTNF on human lung fibroblast IL-6 production. rIL-1 was a potent stimulator, rTNF only marginally stimulated, and rIL-1 and rTNF in combination synergistically stimulated IL-6 protein production. These changes were associated with proportionate alterations in IL-6 mRNA accumulation. Nuclear run-on analysis demonstrated that the effects of rIL-1 and rTNF individually were associated with increased IL-6 gene transcription. In contrast, alterations in gene transcription could not fully explain the synergistic effects of rIL-1 and rTNF in combination. However, IL-6 mRNA was significantly more stable in cells stimulated with rIL-1 plus rTNF than in cells stimulated with rIL-1 alone. Thus the synergistic effects of rIL-1 and rTNF in combination were mediated, at least partially, by an alteration in the stability of IL-6 mRNA. Alterations in mRNA stability may be an important mechanism of cytokine-cytokine synergy.
Elias
J A
JA
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104.
Lentz
V
V
D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha