Assessment of TNFalpha contribution to the functional up-regulation of kinin B(1) receptors in the mouse paw after treatment with LPS.

It has been widely demonstrated that LPS is able to induce kinin B(1) 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 TNFalpha in the functional up-regulation of B(1) receptors in the mouse paw. Systemic treatment with LPS (10 microg/animal, i.v. 24 h before) resulted in a marked increase (about 5-fold) in the mouse paw edema induced by the selective B(1) receptor agonist des-Arg(9)-BK (50 nmol/paw) in both Swiss and C57/BL6 mice. The up-regulation of des-Arg(9)-BK-caused edema following LPS treatment was found to be greatly diminished in TNFalpha p55(-/-) receptor knockout mice. In addition, the paw edema evoked by des-Arg(9)-BK was significantly reduced when mice received the anti-TNFalpha antibody (100 [corrected] microg/kg, i.v.) 5 min before the LPS treatment. A similar inhibition of B(1) receptor-mediated paw edema was observed when mice were treated with thalidomide (30 mg/kg, s.c.) [corrected] a drug known for reducing TNFalpha synthesis, 5 min prior to LPS administration. ELISA experiment [corrected] revealed that TNFalpha 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 TNFalpha is probably responsible for driving the sequence of events involved in the functional up-regulation of B(1) receptors in the mouse paw.