Modulation of antigen‐induced leukocyte adherence inhibition by metabolites of arachidonic acid and intracellular nucleotides

Abstract

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.

Armed human monocytes challenged with a sensitizing cancer extract release substances pharmacologically similar to leukotrienes

“…As little as lo4 M FTL 55712 completely blocked 2.5 X M LTC,, and as little as M FPL 55712 had a similar effect when 2 X lo-" M LTD4 was used. Since we had shown previously that as little as M FPL 55712 was able to inhibit a positive LA1 response (Thomson et a/., 1982), it suggested that as little as 2 X 10-l1 M LTD, produced by monocytes was sufficient to mediate the inhibition of adherence of leukocytes to glass when they bind a sensitizing tumor antigen.…”

“…Antigen-induced leukocyte adherence inhibition is blocked by drugs that block 5-lipoxygenase but not the cyclooxygenase pathway of arachidonic acid metabolism (Thomson et al, 1982). The LA1 phenomenon is prevented by FPL 55712, an antagonist of SRS, suggesting that slow-reacting substances of anaphylaxis (SRS-A), or leukotrienes, are responsible for mediating the LA1 phenomenon (Thomson et al, 1982).…”

“…Antigen-induced leukocyte adherence inhibition is blocked by drugs that block 5-lipoxygenase but not the cyclooxygenase pathway of arachidonic acid metabolism (Thomson et al, 1982). The LA1 phenomenon is prevented by FPL 55712, an antagonist of SRS, suggesting that slow-reacting substances of anaphylaxis (SRS-A), or leukotrienes, are responsible for mediating the LA1 phenomenon (Thomson et al, 1982). Until now it has only been possible to demonstrate the presence of mediators in LA1 assays when the hemocytometer or microplate method was used to assay for activity (Holt et al, 1975;Maluish and Halliday, 1975;Holan et al, 1974Holan et al, ,1981.…”

Diagnostic Value of the Computerized Tube Leukocyte Adherence Inhibition (LAI) Assay for Human Colorectal, Breast and Lung Cancers

“…The same OSN as well as crude extracts from liver metastasis were able to generate the LAI phenomenon. The latter is induced by an arachidonic acid metabolite and is modulated by cyclic AMP levels [17], It is hence not surprising to note that PGE2, which is able to elevate cyclic AMP levels, may have a crucial efTcct on the performance of the LAI assay [18]. In view of the broader knowledge about the LAI phenomenon our results should be evaluated.…”

Purification from a human lung cancer cell line of a water soluble molecule mediating leukocyte adherence inhibition for patients with lung cancer

“…Fetal lungs of 14 to 19 weeks express the OSN epitope, but fetal lungs of 20 weeks do not (Thomson, 1982b), suggesting that the OSN epitope of p40 is expressed during early fetal development and again during oncogenesis. It is not known whether p40 molecules without the OSN epitope are expressed by normal lung tissue.…”