MODULATION OF P2X(7) NUCLEOTIDE RECEPTOR EXPRESSION BY PROINFLAMMATORY AND ANTIINFLAMMATORY STIMULI IN THP-1 MONOCYTES

Regulation of P2X(7) receptor expression is of interest because activa tion of this receptor by extracellular ATP triggers maturation and rel ease of the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) i n monocytes and macrophages. We report that interferon-gamma (IFN-gamm a) and tumor necrosis factor alpha (TNF-a) synergistically induce P2X( 7)R nRNA and functional responses in the human THP-1 monocytic cell li ne. Induction was dose dependent, with maximal functional activity req uiring 1000 units/ml IFN-gamma and 10 ng/mL TNF-alpha and incubations of 36-72 h. The up-regulation of P2X(7)R function by lipopolysaccharid e (LPS)/IFN-gamma and TNF-alpha/IFN-gamma was markedly attenuated by c oincubation with prostaglandin E(2)or the cell permeant cyclic AMP ana log dibutyryl cAMP (Bt(2)cAMP). Bt(2)cAMP did not significantly alter P2X(7) function in HEK-293 cells stably transfected with the human P2X (7) cDNA, indicating that Bt(2)cAMP does not exert a generalized effec t on P2X(7)R synthesis or downstream signal transduction. These studie s demonstrate that elevated cAMP negatively modulates P2X(7)R expressi on.