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 1beta (IL-1beta), 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-1beta were not affected by the surgical procedure, although IL-1beta mRNA levels in PBCs increased significantly. Plasma IL-6 and IL-1Ra increased from 2 to 3 h post-incision onwards. The LPS-induced ex vivo production in WBCs of TNF, IL-1beta 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-1beta production was associated with significantly lower IL-1beta 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.