Post-operative immune suppression is reversible with interferon gamma and independent of IL-6 pathways

Abstract

Introduction The post-operative period is characterised by increased IL-6 production and clinical features of immune suppression. In vitro anti-inflammatory actions of IL-6 are mediated through suppression of interferon gamma (IFNγ) [1]. The clinical significance of IL-6 in mediating post-operative immune suppression remains unclear. Objectives To evaluate the role of IL-6 pathways in post-operative immune suppression and the reversibility of this phenomenon. Methods Patients over 45 years old undergoing elective surgery involving the gastrointestinal tract and requiring at least an overnight hospital stay were recruited. The primary outcome was hospital-acquired infection. IL-6 and IFNγ levels were assayed using ELISA preoperatively and at 24 and 48 hours. Pooled healthy control peripheral blood mononuclear cells (PBMCs) were cultured in perioperative serum and CD14+HLA-DR (mHLA-DR) geometric mean florescent intensity (MFI) measured in the presence and absence of interferon gamma (IFNγ) and IL-6 neutralising antibody. Data were analysed with non-parametric statistics. Results 119 patients were recruited and 44 (37%) developed a post-operative infection a median of 9 (IQR 5-11) days postoperatively (Figure 1). IL-6 levels increased from baseline to 24 hours postoperatively (P < 0.0001, Figure 1A) but were then unchanged between 24 and 48 hours (P = 0.06, Figure 1B). Postoperative IL-6 levels correlated with the duration of the procedure (P = 0.009). Higher preoperative IL-6 levels were observed in patients with cancer (P = 0.02). IL-6 levels at 24 (P = 0.0002) and 48 hours (P = 0.003) were associated with the later occurrence of infectious complications. This pattern remained similar after adjustment for baseline characteristics. Healthy donor PBMCs incubated with postoperative serum downregulated mHLA-DR MFI when compared with serum from baseline (n = 8, p = 0.008). Culturing in the presence of IFNγ 250IU (n = 4) prevented this decrease whereas culturing in the presence of IL-6 neutralising antibody 15ng/ml (n = 8) did not. Conclusions IL-6 levels increase following major surgery and are associated with an increased susceptibility to post-operative infections. Serum obtained from post-operative patients induces an immunosuppressive response through an IL-6 independent pathways which is reversible with IFNγ treatment.