Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes

Regulation of P2X(7) receptor expression is of interest because activation of this receptor by extracellular ATP triggers maturation and release of the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) in monocytes and macrophages. We report that interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-a) synergistically induce P2X(7)R nRNA and functional responses in the human THP-1 monocytic cell line. Induction was dose dependent, with maximal functional activity requiring 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 lipopolysaccharide (LPS)/IFN-gamma and TNF-alpha/IFN-gamma was markedly attenuated by coincubation with prostaglandin E(2)or the cell permeant cyclic AMP analog 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 effect on P2X(7)R synthesis or downstream signal transduction. These studies demonstrate that elevated cAMP negatively modulates P2X(7)R expression.