Immunosuppressive Activity of the Immunophilin‐binding Drug Sanglifehrin A in Human Whole Blood: Potent Inhibition of Interleukin‐6 Produced by Lymphocytes and Monocytes

• Published in: Scandinavian journal of immunology 2006-01, Vol.63 (1), p.26-34
• Main Authors: Härtel, C., Iblher, P., Puzik, A., Wortmeier, K., Ebel, B., Schultz, C., Müller‐Steinhardt, M.
• Format: Article
• Language: English
• Subjects: Cytokines - antagonists & inhibitors; Cytokines - blood; Cytokines - genetics; Humans; Immunophilins - metabolism; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - blood; Interleukin-2 - genetics; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - blood; Interleukin-6 - genetics; Kinetics; Lactones - metabolism; Lactones - pharmacology; Lipopolysaccharides - pharmacology; Monocytes - drug effects; Monocytes - immunology; Monokines - genetics; Monokines - metabolism; RNA, Messenger - blood; RNA, Messenger - metabolism; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/j.1365-3083.2006.01702.x

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)‐α 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‐α 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‐α. 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.