title: Immunosuppressive activity of the immunophilin-binding drug Sanglifehrin A in human whole blood: potent inhibition of interleukin-6 produced by lymphocytes and monocytes.
abstract: The novel immunosuppressant Sanglifehrin A (SFA) is an immunophilin-binding metabolite with a yet unidentified mechanism of action. Several reports demonstrated the effects of SFA on proliferation and cytokine production of purified T cells with in part different results. However, less is known about the impact of SFA on the regulation of innate immune responses. We used a whole blood assay to investigate the impact of SFA on monocyte responses and T-lymphocyte activity/proliferation upon lipopolysaccharide (LPS) stimulation and anti-CD3/anti-CD28 costimulation, respectively. SFA was found to inhibit interleukin (IL)-2 protein expression of T lymphocytes. Whereas IL-2 mRNA expression was significantly reduced after 4 h of costimulation, the mRNA expression of IL-4 and IL-6 but not tumour necrosis factor (TNF)-alpha was inhibited by SFA both after 4 and 24 h of costimulation. The production of IL-2 and IL-6 protein in T lymphocytes was even strongly affected by SFA than the mRNA expression of the respective cytokine. Unlike other immunophilin-binding immunosuppressants, SFA also inhibited LPS-induced IL-6 and TNF-alpha mRNA and protein expression. At the single cell level, SFA was demonstrated to block the intracellular production of IL-6 in CD14+ monocytes but not the expression of other proinflammatory cytokines such as IL-8 and TNF-alpha. On the basis of these data, we propose that SFA may have a significant effect on the initiation and direction of immune responses. Considering the pleiotropic role of bioactive IL-6 production at the interface of innate and acquired immunity in a variety of disease conditions, it was found that these novel aspects of the unique immunosuppressive action could strongly impact on future clinical application of SFA.
authors.affiliation: Department of Pediatrics, University of Lübeck Medical School, Ratzeburger Allee, Lübeck, Germany. haertel@paedia.ukl.mu-luebeck.de
authors.forename: C
authors.initials: C
authors.lastname: Härtel
authors.forename: P
authors.initials: P
authors.lastname: Iblher
authors.forename: A
authors.initials: A
authors.lastname: Puzik
authors.forename: K
authors.initials: K
authors.lastname: Wortmeier
authors.forename: B
authors.initials: B
authors.lastname: Ebel
authors.forename: C
authors.initials: C
authors.lastname: Schultz
authors.forename: M
authors.initials: M
authors.lastname: Müller-Steinhardt
mesh_terms: D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D007700:Kinetics; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D015846:Monokines / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D016207:Cytokines; D020104:Immunophilins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015850:Interleukin-6; D007783:Lactones; D008070:Lipopolysaccharides; D015846:Monokines; D012333:RNA, Messenger; D013141:Spiro Compounds; D000093242:Interleukin-6 Inhibitors; C121329:sanglifehrin A