Role of endogenously derived leukotrienes in the regulation of lysosomal enzyme expression in macrophages exposed to beta 1,3-glucan

• Published in: Journal of leukocyte biology Vol. 49; no. 3; pp. 266 - 276
• Main Authors: Lew, D. Betty, Leslie, Christina C., Henson, Peter M., Riches, David W.H.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Society for Leukocyte Biology 01.03.1991; Federation of American Societies for Experimental Biology
• Subjects: 5,8,11,14-Eicosatetraynoic Acid - pharmacology; Analysis of the immune response. Humoral and cellular immunity; Animals; autocrine regulation; Benzoquinones - pharmacology; beta-Glucans; beta-N-Acetylhexosaminidases - metabolism; Biological and medical sciences; Cyclooxygenase Inhibitors; Dinoprostone - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glucans - pharmacology; Immunobiology; Indomethacin - pharmacology; Leukotrienes - physiology; Lipoxygenase Inhibitors; lysosomal enzyme hexosaminidase; Lysosomes - enzymology; Macrophages - enzymology; Male; Mice; Mice, Inbred BALB C; mouse macrophages; Organs and cells involved in the immune response; Phospholipases A - metabolism; Phospholipases A2; priming; SRS-A - metabolism; yeast cell walls; Yeast; Enzyme; Arachidonic acid derivatives; Rodentia; Lysosome; Hexosaminidase; Glucan; Vertebrata; Mammalia; Enzymatic activity; Mouse; Leukotriene C4; Sensitization; Macrophage
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1002/jlb.49.3.266

The expression of the lysosomal enzyme hexosaminidase has been shown to be stimulated by the exposure of mouse macrophages to β 1,3‐glucan, a particulate component of yeast cell walls and zymosan particles. Exposure of mouse peritoneal macrophages to particulate β 1,3‐glucan (100 μg/ml) was also found to stimulate the production of eicosanoids from both the cyclooxygenase (prostaglandin E2) and 5′‐lipoxygenase (leukotriene C4) pathways. The objective of this study was to determine the relationship, if any, between the production of arachidonic acid metabolites and the increased expression of lysosomal enzymes. To determine if products of the cyclooxygenase or 5′‐lipoxygenase pathway were involved in the regulation of hexosaminidase expression, macrophages were exposed to β 1,3‐glucan in the presence of indomethacin, an inhibitor of cyclooxygenase; 4,7,10,13 ETYA, an inhibitor of both cyclooxygenase and 5′‐lipoxygenase; or AA861, a selective inhibitor of 5′‐lipoxygenase. While the increased expression of hexosaminidase was not affected in macrophages stimulated with β 1,3‐glucan in the presence of indomethacin, both 4,7,10,13 ETYA and AA861 completely blocked the response, suggesting a role for products of the 5′‐lipoxygenase pathway in the regulation of hexosaminidase expression. To further explore the relationship between arachidonate release and the increased expression of hexosaminidase, macrophages were exposed to phospholipase A2 in an attempt to circumvent the interaction between β 1,3‐glucan and the macrophage membrane. Incubation with phospholipase A2 was found both to induce the accumulation of LTC4 in the culture supernatant and to stimulate the increased expression of hexosaminidase. The mechanism of regulation of hexosaminidase expression by products of the 5′‐lipoxygenase pathway was investigated by incubating macrophages with purified luekotrienes in either the presence or absence of β 1,3‐glucan. Incubation of macrophages with purified LTC4 or LTB4 in the absence of β 1,3‐glucan failed to stimulate the expression of hexosaminidase. However, challenging macrophage monolayers with LTC4 or LTB4 in the presence of a suboptimal concentration of β 1,3‐glucan (1 μg/ml) led to a synergistic increase in the expression of hexosaminidase. Collectively these data suggest that the leukotriene products of the 5′‐lipoxygenase pathway, LTC4 and LTB4, regulate the expression of lysosomal enzymes by apparently priming macrophages, thereby increasing their sensitivity to triggering agents such as β 1,3‐glucan. Since macrophages produce LTC4, and the increased expression of hexosaminidase is prevented by inhibitors of the 5′‐lipoxygenase pathway, the data further suggest that LTC4 may prime macrophages in an autocrine or paracrine fashion.