LOCAL CYTOKINE INDUCTION BY LPS IN THE RAT AIR POUCH AND ITS RELATIONSHIP TO THE FEBRILE RESPONSE

Peripheral induction of cytokines is a critical event in the induction of febrile responses. The sequence of induction and site of action of these cytokines, however, remain unclear. The objective of the presen t study was to investigate the kinetics of local and systemic producti on of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), with the aim of identifying the relationship between these cytokines and th e febrile response induced by injection of lipopolysaccharide (LPS) in to a subcutaneous air pouch in the rat. Intrapouch injection of LPS in duced dose-dependent fevers and increases in the concentration of bioa ctive IL-6 in the plasma. Further studies using 100 mu g/kg LPS demons trated significant increases in local (air pouch) concentrations of bi oactive IL-1, TNF and IL-6, and circulating IL-6. No significant incre ases in TNF or IL-1 were detected in the plasma of the same animals. L ocal TNF was induced rapidly and peaked 1 h after LPS injection. The k inetics of local IL-1 and IL-6 induction were similar and both peaked after 3 h. The rise in local IL-6 preceded that of plasma IL-6 and rea ched a peak concentration that was 25-fold higher than that observed i n the plasma. The data indicate that IL-1 and TNF act locally at the s ite of inflammation and that locally induced IL-6 is the important sys temic mediator of the response.