Modulation of lymphocyte activation. I. Inhibition by an oxidation product of arachidonic acid
Goodman, M.G.; Weigle, W.O.
Journal of Immunology 125(2): 593-600
1980
ISSN/ISBN: 0022-1767 PMID: 6156209 Document Number: 164519
Proliferation and maturation of murine splenocytes are profoundly inhibited by incubation with the oxidation product(s) generated from soybean lipoxidase-treated arachidonic acid (AA/L). The major oxidation product generated was the 15-hydroperoxide of arachidonic acid (AA), which in purified form exerted potent inhibitory activity. Inhibition was unaltered by addition of the prostaglandin synthetase inhibitor, indomethacin, to cultures containing AA/L. AA/L interfered with RNA synthesis protein synthesis, DNA synthesis and blastogenesis, all with parallel inhibition profiles, without adversely affecting cellular viability. Various lymphocyte subpopulations, distinguished by reactivity to different mitogens [concanavalin A, Mycobacterium tuberculosis purified protein derivative, Poly-IC], were all equally inhibited by addition of AA/L to culture. Growth of the mastocytoma cell line, P-815, was arrested in the presence of the lipoxidase-catalyzed oxidation product(s) of AA, indicating that the mechanism of AA/L-mediated inhibition did not necessitate interference with receptor-ligand interaction. Proliferative and polyclonal responses to bacterial lipopolysaccharide [LPS] were inhibited even when AA/L was added as late as 24 h after initiation of culture. Whereas a 10-30 min preincubation with AA/L at 37.degree. C was sufficient to inhibit mitogenesis totally, preincubation at 4.degree. C led to only partial inhibition, indicating that inhibition is, at least in part, an active process. The inhibitory activity mediated by AA/L could not be reversed in its absence in recovery periods up to 6 h before addition of LPS. Possible implications of these observations for understanding cellular activation mechanisms are discussed.