Modulation of antigen-induced leukocyte adherence inhibition by metabolites of arachidonic acid and intracellular nucleotides.
After binding a sensitizing tumor antigen, human leukocytes undergo a series of changes that lead to a loss of their glass-adherent properties; a phenomenon called leukocyte adherence inhibition (LAI). After surgery or when patients have a large tumor burden, their test results become negative. This study shows that in vitro incubation of the leukocytes for 5 min with PGE2 converted to positive the negative test, in an immunologically specific manner. The effect was critically dose-dependent, too little or too much did not alter the result. The same effect was achieved with PGE2, PGI2, aminophylline or other drugs that raise intracellular nucleotides, including dibutyryl cyclic AMP and dibutyryl cyclic GMP. Dibutyryl cyclic AMP stimulated a stronger response and 100 times less was needed than of dibutyryl cyclic GMP. Prostaglandins did not mediate LAI since Indomethacin failed to inhibit a positive test. Nonetheless, arachidonate metabolites were critical for the LAI phenomenon since BPB and mepacrine, inhibitors of phospholipase A2, negated the LAI response. Moreover, ETYA, phenidone and NDGA, inhibitors of the lipoxygenase metabolic pathway, all negated the positive LAI response. The positive response was especially sensitive to nullification by ETYA. Although the last-named drugs inhibit other arachidonate metabolic pathways too, conclusive evidence that the metabolites of the lipoxygenase pathway, and leukotrienes in particular, mediate the LAI response was the fact that FPL 55712, a competitive antagonist of SRS, nullified a positive response at levels as low as 10(-13) M. The results imply that prostaglandins were able to modulate the expression of LAI by affecting intracellular nucleotides, but leukotrienes, it seems, were the metabolites that mediated leukocyte nonadherence after monocytes recognized and bound tumor antigen.
D000951:Antigens, Neoplasm / Q000276:immunology; D000975:Antioxidants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D015232:Dinoprostone; D006801:Humans; D007158:Immunologic Techniques; D007213:Indomethacin / Q000494:pharmacology; D007957:Leukocyte Adherence Inhibition Test; D009637:Masoprocol; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011458:Prostaglandins E / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000975:Antioxidants; D001095:Arachidonic Acids; D002396:Catechols; D011458:Prostaglandins E; D009637:Masoprocol; D015232:Dinoprostone; D007213:Indomethacin