THE DECREASE IN NONSPLENIC INTERLEUKIN-6 (IL-6) PRODUCTION AFTER SPLENECTOMY INDICATES THE EXISTENCE OF A POSITIVE FEEDBACK LOOP OF IL-6 PRODUCTION DURING ENDOTOXEMIA IN DOGS

The spleen is involved in endotoxin-induced interleukin-6 (IL-6) produ ction, To quantitate the relative contribution of the spleen to endoto xin-induced IL-6 production, we studied the effect of endotoxin (1.0 m u g/kg of body weight) in control dogs (n = 7) and splenectomized dogs (n = 7), Blood for analysis of tumor necrosis factor (TNF) and IL-6 w as sampled from the femoral artery and the portal, hepatic, and spleni c (only in controls) veins, Arterial plasma endotoxin and cortisol lev els were also measured, Whole-body IL-6 production was calculated by a deconvolution technique, Splenic IL-6 production in control dogs was measured from splenic blood flow and arteriovenous concentration diffe rences, Endotoxin levels were higher in splenectomized dogs (P < 0.05) because of a decreased distribution volume (P < 0.05) and decreased c learance of endotoxin (P < 0.05), Endotoxin-induced plasma IL-6 levels were decreased by similar to 75% in splenectomized dogs (P < 0.01), a nd whole-body IL-6 production rates were severalfold lower (median of 8.7 mg/4 h and range of 3.9 to 11.4 mg/4 h versus a median of 32.3 mg/ 4 h and a range of 22.7 to 70.2 m/4 h) (P < 0.05), However, in control dogs splenic IL-6 production (0.6 +/- 0.2 mg/4 h) was only similar to 2% of whole-body IL-6 production, Plasma TNF levels increased in both groups (P < 0.01) but were not different between the groups. Plasma c ortisol levels were slightly higher in splenectomized dogs than in con trol dogs (P < 0.05), In conclusion, splenectomy decreases the distrib ution volume and clearance rate of endotoxin, Splenectomy results in d ecreased endotoxin-induced IL-6 production, which is caused not by the absence of splenic IL-6 production, but by a decrease in nonsplenic I L-6 production. Therefore, the spleen is an important mediator in the complete activation of nonsplenic IL-6 production by endotoxin.