In vivo administration of 15-deoxyspergulin inhibits antigen-presenting cell stimulation of T cells and NF-kappaB activation.
15-Deoxyspergulin (DSG), a synthetic derivative of spergulin, was initially characterized for its antibiotic and antitumor effects. Recent studies have described the immunosuppressive properties of this molecule, but its mechanism of action is not clearly understood. In the study reported here, mice were treated in vivo with DSG prior to the measurement of IL-2 production and proliferation in an in vitro antigen presentation assay. At suboptimal antigen concentrations, elicited peritoneal macrophages or percoll isolated B cells from DSG-treated mice showed a 50-96% reduction in their ability to present chicken ovalbumin (cOva), cOva peptide, or superantigen (SAg) to MHC class II-matched antigen-specific primary T cells. No significant changes could be found in the cell surface expression of CD80, CD86, MHC I, MHC II, CD18, CD11b, CD40, CD25, and CD54 in antigen-presenting cells (APC) from control or DSG-treated animals. Activation with SAg of macrophages or splenocytes from DSG-treated mice revealed that there was a significant reduction in nuclear NF-kappaB levels compared to cells from untreated animals. Additionally, analysis of cytokines showed that production of TNF-alpha and IL-1beta was inhibited in cultures where macrophages from DSG-mice were used to present cOva to T cells. These results indicate that the effects of DSG in mice are not simply due to altered antigen processing or from any marked changes in cell surface antigen expression. Rather, the immunosuppression may arise from alterations in the release of one or more soluble factor from DSG-treated APC, which prevents effective antigen presentation and T cell activation.
Diegel
Michael L
ML
Department of Immunology and Inflammation, Bristol Myers-Squibb Pharmaceutical Research Institute Princeton, NJ 08543-4000, USA.
Nadler
Steven G
SG
Kiener
Peter A
PA
D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000502:physiology; D000954:Antigens, Surface / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D000954:Antigens, Surface; D016207:Cytokines; D006146:Guanidines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; C037258:gusperimus