Features of Postoperative Immune Suppression Are Reversible with Interferon Gamma and Independent of Interleukin-6 Pathways

Objective: The aim of this study was to evaluate the role of interleukin (IL)-6 pathways in postoperative immune suppression and to assess the reversibility of this phenomenon. Background: The postoperative period is characterized by increased IL-6 production and features of immune suppression. In vitro, IL-6 mediates anti-inflammatory effects through inhibition of interferon gamma (IFN-γ) pathways. The significance of the immunomodulatory effects of IL-6 in the clinical setting of postoperative immune suppression remains unclear. Methods: Patients over 45 years old undergoing elective surgery, involving the gastrointestinal tract, were recruited. IL-6 levels were assayed using an enzyme linked immunosorbent assay preoperatively, and at 24 and 48 hours. Peripheral blood mononuclear cells from healthy volunteers were cultured in perioperative serum and CD14 + Human Leukocyte Antigen-DR (HLA-DR) [monocyte HLA-DR (mHLA-DR)] geometric mean florescent intensity was measured in the presence and absence of IL-6 neutralizing antibody and recombinant IFN-γ. Results: Of the 108 patients, 41 developed a postoperative infection. The IL-6 levels increased 19-fold from the preoperative sample to 24 hours postoperatively (P<0.0001). Higher IL-6 levels at 24 (P=0.0002) and 48 hours (P=0.003) were associated with subsequent postoperative infectious complications. mHLA-DR mean florescent intensity fell when healthy peripheral blood mononuclear cells were cultured with postoperative serum compared with preoperative serum (P=0.008). This decrease was prevented by the presence of IFN-γ in the culture media, but not by the presence of IL-6-neutralizing antibody. Conclusions: IL-6 levels increase after a major surgery and are associated with an increased susceptibility to postoperative infections. Serum obtained from postoperative patients induces an immunosuppressive response, reflected in reduced mHLA-DR levels, mediated through IL-6 independent pathways and is reversible with IFN-γ. These data may have therapeutic implications for the prevention of infection in patients undergoing major surgery. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved

Cancer cell senescence: a new frontier in drug development

Senescence forms a universal block to tumorigenesis which impacts on all hallmarks of cancer, making it an attractive target for drug discovery. Therefore a strategy must be devised to focus this broad potential into a manageable drug discovery programme. Several issues remain to be addressed including the lack of robust senescence-inducing compounds and causally related biomarkers to measure cellular response. Here, we review the latest progress in translating senescence as a target for cancer therapy and some promising approaches to drug and biomarker discovery. Finally, we discuss the potential application of a senescence-induction therapy in a clinical setting