Transthyretin is an inhibitor of monocyte and endothelial cell interleukin-1 production.
Human serum was found to contain an inhibitor of constitutive interleukin-1 (IL-1) production by human umbilical vein endothelial cells (ECs). Purification of the serum activity by anion exchange chromatography, molecular sieve HPLC, and hydroxyl apatite chromatography yielded material 82% pure with a molecular weight of 17 kDa by SDS-PAGE. Amino acid sequencing revealed the purified inhibitor to be transthyretin (TTR), a liver-derived protein. There was a 42.6% reduction in the production of spontaneous IL-1 activity in EC supernatants after coculture with 10 micrograms/ml TTR. TTR was subsequently found by ELISA to inhibit LPS-stimulated IL-1 production by cells of the human monocytic leukemia line THP-1 by 47.1 +/- 9.4%, whereas a less striking but still significant inhibition of monocyte-derived IL-1 beta production was also observed. Inhibition of IL-1 secretion correlated with increased IL-1 mRNA synthesis in both THP-1 cells and monocytes. Furthermore, TTR was associated with increased intracellular concentrations of IL-1 beta. These data suggest that TTR functions by inhibiting processing of newly synthesized peptide for secretion. This novel inhibitory effect of TTR on the production of IL-1 activity suggests a previously unrecognized endogenous antiinflammatory mediator.
Borish
L
L
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, University of Colorado Health Sciences Center, Denver 80206.
King
M S
MS
Mascali
J J
JJ
Johnson
S
S
Coll
B
B
Rosenwasser
L J
LJ
D000595:Amino Acid Sequence; D001681:Biological Assay; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D011228:Prealbumin / Q000302:isolation & purification / Q000502:physiology*; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011228:Prealbumin; D012333:RNA, Messenger; D012313:RNA