Disruption of sphingolipid homeostasis by myriocin, a mycotoxin, reduces thymic and splenic T-lymphocyte populations.
Myriocin is a naturally occurring fungal metabolite possessing potent immunosuppressive properties. The biochemical mechanism of action of this compound is inhibition of serine palmitoyltransferase (SPT), the key rate limiting enzyme in sphingolipid biosynthesis, intermediates of which are important mediators of immune signaling. Previous studies have shown that myriocin strongly suppressed immune function with T-lymphocyte functions being most sensitive. To further our understanding of the mechanisms of this effect, we investigated the impact of subacute treatment with myriocin on lymphocyte populations in the thymus and spleen of male BALB/c mice following intraperitoneal injection of myriocin at 0, 0.1, 0.3, and 1.0 mg/kg daily for 5 consecutive days. Cellular analysis of the thymus demonstrated that total cellularity was dose-dependently reduced and the reduction was significant in mice treated with 1.0 mg/kg myriocin. Phenotyping showed that CD4+ and CD4+/CD8+ double positive lymphocyte populations were sensitive to myriocin. No change in total cellularity of the spleen was noted but there was a significant reduction in the CD4+ lymphocyte population in mice treated with 1.0 mg/kg myriocin. There was a strong positive correlation between total CD4+ lymphocytes in the thymus and those in the spleen. Analysis of sphingolipid levels showed a dose-dependent reduction of sphinganine in the thymus, which were positively correlated with all reductions in lymphocyte populations. These results suggest that the immunosuppressive properties of myriocin may be due to diminished T-lymphocyte populations likely related to inhibition of SPT and disruption of sphingolipid homeostasis.
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Victor J
VJ
Johnson
Quanren
Q
He
Marcin F
MF
Osuchowski
Raghubir P
RP
Sharma
D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity*; D005434:Flow Cytometry; D006706:Homeostasis / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids / Q000096:biosynthesis* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects*
D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D013107:Sphingolipids; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse; C001996:thermozymocidin