However, in previous studies inhibition of HSP90 by GA was shown to diminish NF-κB activity in tumor cells due to impaired expression of the NK-κB signaling regulators IKK [15], NIK [16], and RIP1 [17]. Limited activity of either regulator may contribute to attenuated RelB

expression in stimulated MO-DCs cotreated with GA. In T cells GA may inhibit the expression of the tyrosine kinase lck, and impair its stimulation-induced phosphorylation as evidenced in a human T cell line (Jurkat) [52, 53]. Due to this early block in T cell activation, IL-2 production of stimulated T cells was largely abrogated. Most recently, GA was demonstrated to affect as well the expression of several T cell receptor-associated molecules, namely TCRαß, CD4 and CD28 [54]. In accordance, GA prevented the proliferation of lymphocytes treated with stimulatory this website antibodies [53] and of T cells stimulated by either MO-DCs or mitogen [54]. In line, we observed largely abrogated proliferation of CD4+ T cells stimulated DAPT solubility dmso by unstimulated or stimulated MO-DCs or by application of stimulatory antibodies. Conclusions Our study has shown that GA-mediated inhibition of HSP90 in unstimulated MO-DCs may result in partial activation of the cells by yet unknown mechanisms. On the other hand, GA treatment

impaired MO-DC stimulation and largely abrogated both polyclonal and DC-mediated T cell proliferation. Chemotherapeutics that act to inhibit HSP90 may therefore exert rather inhibitory effects on the patients’ immune system, and most likely are not preferable for combination Plasmin with immunotherapy that targets the DC/T cell axis to mount potent anti-tumor responses. Acknowledgements We thank Claudia Eider and Dr. Dirk Prawitt (both Center for Pediatrics and Adolescent Medicine, University Medical Center

of the Johannes Gutenberg-University, Mainz, Germany) for providing us with the cell line IGROV1. This study was supported by grants of the University Medical Center Mainz (MAIFOR program), and of the Deutsche Forschungsgemeinschaft (grant number RE 617/1-1). Stefanie Trojandt did partial fulfillment of the requirements of the doctoral thesis. Electronic supplementary material Additional file 1: Table S1: GA affects surface marker expression by MO-DCs in an activation state-dependent manner. (DOC 37 KB) Additional file 2: Figure S1: GA slightly reduces the endocytotic activity of unstimulated MO-DCs. (TIFF 2 MB) Additional file 3: Figure S2: MO-DCs acquire potent T cell stimulatory capacity in response to stimulation. (TIFF 760 KB) References 1. da Silva VC, Ramos CH: The network interaction of the human cytosolic 90 kDa heat shock protein Hsp90: a target for cancer therapeutics. J Proteomics 2012, 75:2790–2802.PubMedCrossRef 2. Echeverría PC, Bernthaler A, Dupuis P, Mayer B, Picard D: An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine.