The role of local induction of tumor necrosis factor by LPS within a subcutaneous air pouch in the development of a febrile response in guinea pigs

In rats, fever can be induced by injection of bacterial lipopolysaccharide (LPS) into a subcutaneous air pouch. This febrile response is in part depen dent on the local action of interleukin-1 beta within the pouch. In the pre sent study, we tried to find out if this model of fever induction can be ap plied in guinea pigs and if the local LPS-induced formation of tumor necros is factor-alpha (TNF-alpha) participates in the development of the febrile response. A dose of 100 mu g/kg LPS was injected into a subcutaneous air po uch along with solvent (0.9% saline), or 100 mg/kg pentoxifylline, or 1 mg/ animal soluble 55-kD TNF receptor (referred to as TNF-binding protein, TNF bp). The mean LPS-induced concentration of TNF in the ravage of the air pou ch (measured 60 min after injection) was 17,765 pg/ mi in animals injected with LPS and solvent. This value was reduced to 7,631 pg/ml if pentoxifylli ne was injected along with LPS into the pouch. If LPS was injected along wi th TNF bp, no bioactive TNF was detected in the lavage of the air pouch. Si multaneously, TNF was measured in blood plasma. Circulating concentrations of TNF were about 5-8% of the values detected in the lavage of the air pouc h (mean values: 1,366 pg/ml in response to LPS plus solvent; 377 pg/ml in r esponse to LPS plus pentoxifylline; no circulating TNF at all in response t o LPS plus TNF bp). These data indicated a small spill-over of TNF from the air pouch into the circulation. Neither the reduction of local TNF formati on in the air pouch by pentoxifylline nor the complete neutralization of TN F within the pouch by TNF bp resulted in a significant attenuation of the f ebrile response induced by injection of LPS into the subcutaneous air pouch . If there were an activation of cutaneous nerves to induce fever by a loca l formation of cytokines within the air pouch, TNF would not represent a li kely candidate to be responsible for such a neural stimulation. Copyright ( C) 2000 S. Karger AG. Basel.