Induction of pulmonary granulomas, macrophage procoagulant activity, and tumor necrosis factor-alpha by trehalose glycolipids
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C A Behling1, R L Perez, M R Kidd
1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
Abstract:
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.
Insights
Trehalose 6,6' dimycolate (TDM) forms structured layers, causing toxicity. Its unique surface structure, not analogs, is necessary for inducing pulmonary granulomas and inflammatory responses.
Area of Science:
- Immunology
- Biochemistry
- Microbiology
Background:
- Trehalose 6,6' dimycolate (TDM) is a mycobacterial glycolipid.
- TDM induces granulomas and toxic reactions when delivered in oil, but not saline.
- Previous work showed TDM forms structured layers at oil-water interfaces, suggesting adhesive properties contribute to toxicity.
Purpose of the Study:
- To test the hypothesis that TDM's toxicity is due to its adhesive surface layers.
- To evaluate TDM and analogs (TMM, GDM) for their ability to induce pulmonary granulomas.
- To assess the stimulation of procoagulant activity (PCA) and tumor necrosis factor-alpha (TNF-alpha) by TDM and analogs.
Main Methods:
- Intravenous injection of oil-in-water emulsions of TDM, TMM, and GDM into mice.
- Analysis of pulmonary granuloma formation.
- Incubation of human mononuclear cells with TDM, TMM, and GDM on bead surfaces.
- Measurement of PCA and TNF-alpha expression.
Main Results:
- TDM induced significantly more and larger pulmonary granulomas compared to TMM and GDM.
- TDM stimulated higher levels of PCA and TNF-alpha in human mononuclear cells than its analogs.
- Results correlate with the distinct surface layer structures formed by TDM.
Conclusions:
- The specific surface structure formed by TDM is crucial for its biological activity.
- Adhesive properties of TDM's structured layers likely contribute to its toxicity.
- TDM's unique surface properties drive granuloma formation and inflammatory mediator release.