Amplification of extracellular nucleotide-induced leukocyte(s) degranulation by contingent autocrine and paracrine mode of leukotriene-mediated chemokine receptor activation.

Extracellular nucleotide-induced stimulation and activation of peripheral blood leukocytes and subsequent degranulation play a critical role in immediate-type hypersensitivity reaction and other inflammatory diseases. The extracellular nucleotides stimulate a P2Y receptor(s) on human PMN with the pharmacological profile similar to that of the P2Y2 receptor. Upon activation of P2Y2, arachidonic acid, formed from the membrane bound lipids by phospholipase A2, which subsequently metabolized by 5-lipoxygenase to form the leukotrienes. Of the several leukotrienes generated, LTB(4) is a potent pro-inflammatory chemokine. Upon its release LTB(4) binds to the PMN in a paracrine manner and also other leukocytes such as monocytes at the site of vascular injury, leading to an accelerated rate of degranulation. It is known that LTA(4) formed in the 5-lipoxygenase pathway in PMN could be released from PMN by receptor-mediated transport. Upon its release, the monocytes, erythrocytes, platelet, endothelial or smooth muscle cells can take up LTA(4). The endogenous LTA(4) hydrolase form the LTB(4) from LTA(4) in erythrocytes, platelet, endothelial or smooth muscle cells. As in PMN, LTB(4) is released from these cells via receptor-mediated transport to the extracellular milieu. Thus, released LTB(4) most likely acts as potentially accelerating factor in PMN and MN degranulation through its receptor-specific binding. It is not known whether any LTB(4) receptor exists in cytoplasm in any given cell type and also, the existence of any other signaling cascade for the extracellular nucleotide-induced leukocyte degranulation. Thus, it is convincing that the extracellular nucleotides released from the activated platelets and other damaged cell types exacerbate the inflammatory response by leukotriene generation. In turn the leukotriene will act in both autocrine and paracrine manner to amplify the degranulation processes in leukocytes invoked by extracellular nucleotides.