Effect of L-cycloserine on cellular responses mediated by macrophages and T cells.
In this study, we examined the immunoregulatory roles of L-cycloserine (L-CS), a sphingolipid metabolism regulator with inhibitory activity of serine palmitoyltransferase (SPT), on immune responses mediated by monocytes/macrophages and T cells. Mitogenic responses of splenic lymphocytes induced by LPS, PHA, and Con A were very strongly suppressed by L-CS with IC(50) values ranging from 0.5 to 1 muM. In contrast, this compound less strongly blocked IL-2-induced CD8+ CTLL-2 cell proliferation with an IC(50) value of 540 muM. Interestingly, L-CS enhanced the number of IL-4-producing helper T cells, indicating the favored induction of Th2 condition. Although tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production was not altered under 10% FCS condition, U937 cell-cell adhesion as well as the surface level of adhesion molecules (CD29 and CD98) were significantly suppressed by L-CS. In particular, reduced serum level (5%) under L-CS treatment strongly enhanced the production of TNF-alpha and the inhibitory potency of NO production and cell adhesion. Finally, sphingolipids (D-sphingosine and DL-dihydrosphingosine) did not remarkably abrogate L-CS-mediated T cell proliferation. Therefore our data suggest that de novo sphingolipid metabolism may represent an important aspect of immunomodulatory activities mediated by T cells and macrophages/monocytes, depending on serum level.
Cho
Jae Youl
JY
School of Bioscience and Biotechnology and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Korea. jaecho@kangwon.ac.kr
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003523:Cycloserine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005562:Formazans / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D013778:Tetrazolium Salts / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D005562:Formazans; D007376:Interleukin-2; D013778:Tetrazolium Salts; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C079782:MTT formazan; D009569:Nitric Oxide; D003523:Cycloserine