Assessment of TNFα contribution to the functional up-regulation of kinin B1 receptors in the mouse paw after treatment with LPS

It has been widely demonstrated that LPS is able to induce kinin B1 receptor up-regulation throughout several models of inflammation. Using an in-vivo system in which LPS was administered systemically, we assessed the participation of the pro-inflammatory cytokine TNFα in the functional up-regulation of B1 receptors in the mouse paw. Systemic treatment with LPS (10 μg/animal, i.v. 24 h before) resulted in a marked increase (about 5-fold) in the mouse paw edema induced by the selective B1 receptor agonist des-Arg9-BK (50 nmol/paw) in both Swiss and C57/BL6 mice. The up-regulation of des-Arg9-BK-caused edema following LPS treatment was found to be greatly diminished in TNFα p55−/− receptor knockout mice. In addition, the paw edema evoked by des-Arg9-BK was significantly reduced when mice received the anti-TNFα antibody (500 μg/kg, i.v.) 5 min before the LPS treatment. A similar inhibition of B1 receptor-mediated paw edema was observed when mice were treated with thalidomide (30 mg/kg, s.c), a drug known for reducing TNFα synthesis, 5 min prior to LPS administration. ELISA experiments revealed that TNFα serum levels were maximal at 1 h following LPS systemic treatment. Taken together, the present results suggest that the early production of the pro-inflammatory cytokine TNFα is probably responsible for driving the sequence of events involved in the functional up-regulation of B1 receptors in the mouse paw.