Induction of pulmonary granulomas, macrophage procoagulant activity, and tumor necrosis factor-alpha by trehalose glycolipids.
Trehalose 6,6' dimycolate (TDM), a mycobacterial glycolipid, induces granulomas and hemorrhagic toxic reactions when administered in oil but not as a suspension in saline. It was previously demonstrated by us that TDM forms highly structured layers at oil-water interfaces and then postulated that its toxicity derives from the adhesive properties of these layers. To test this hypothesis, an evaluation was made of the ability of TDM and two analogs, trehalose 6-monomycolate (TMM) and galactose-galactose 6, 6' dimycolate (GDM), to induce pulmonary granulomas and stimulate expression of procoagulant activity (PCA) and tumor necrosis factor-alpha (TNF-alpha). Intravenous injection in mice of oil-in-water emulsions of TDM produced more and larger pulmonary granulomas than injection of TMM or GDM. Similarly, TDM on the surface of beads induced higher levels of PCA and TNF-alpha in human mononuclear cells than the analogs. The correlation of these results with the structure of surface layers of the glycolipids strengthens the hypothesis that the particular surface structure formed by TDM is necessary for its biologic activity.
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
C A
CA
Behling
R L
RL
Perez
M R
MR
Kidd
G W
GW
Staton
R L
RL
Hunter
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D003311:Cord Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004655:Emulsions; D005260:Female; D006099:Granuloma / Q000139:chemically induced*; D008171:Lung Diseases / Q000139:chemically induced*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D003311:Cord Factors; D004655:Emulsions; D014409:Tumor Necrosis Factor-alpha