Elective orthopedic surgery, a model for the study of cytokine activation and regulation

Induction and downregulation of cytokine production occurs after contact with various inflammatory stimuli. To elucidate the early events after a physical stressor, we studied these processes in 13 patients undergoing elective total hip replacement surgery. In these patients we followed the plasma concentrations of tumour necrosis factor alpha (TNF), interleukin 1 beta (IL-1 beta), IL-6 and IL-1 receptor antagonist (IL-1Ra), mRNA for these cytokines in peripheral blood cells (PBCs), and the lipopolysaccharide(LPS) -stimulated ex vivo production of these cytokines in whole blood cultures (WBCs). Plasma TNF and IL-1 beta were not affected by the surgical procedure, although IL-1 beta mRNA levels in PBCs increased significantly. Plasma IL-6 and IL-1Ra increased from 2 to 3h post-incision onwards. The LPS-induced ex vivo production in WBCs of TNF, IL-1 beta and IL-6 decreased from 2 h post-incision; that of IL-1Ra increased. Downregulation of TNF production was not associated with lower TNF-mRNA suggesting post-transcriptional regulatory processes. In contrast, downregulation of IL-1 beta production was associated with significantly lower IL-1 beta mRNA, suggesting both post-transcriptional and transcriptional mechanisms. Remarkably, the increase of plasma IL-6 occurred when the IL-6 production ex-vivo in WBCs was maximally downregulated. This suggests that other immunocompetent cells and not PBCs are the source for plasma IL-6 and that the IL-6 production in those other cells might be regulated differentially.