Inhibition of human mononuclear cell proliferation, interleukin synthesis, mRNA for IL-2, IL-6, and leukotriene B4 synthesis by a lipoxygenase inhibitor

Abstract

Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro with various stimuli and in the presence or absence of a 5-lipoxygenase (5-LO) inhibitor, A-63162, to measure its effects on PBMC proliferation, interleukin-2 receptor (IL-2R) expression, interleukin-2 (IL-2) synthesis, interleukin-6 (IL-6) synthesis, and accumulation of messenger RNA for IL-2 or IL-6. A-63162 inhibited PBMC proliferation stimulated by phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) plus A23187, IL-2 receptor expression stimulated by PHA, and IL-2 or IL-6 synthesis induced by PHA plus PMA or PMA plus A23187. At the same concentration, A-63162 inhibited accumulation of mRNA for IL-2 or IL-6 and also inhibited leukotriene B4 (LTB4) synthesis. Our data indicate that the 5-LO inhibitor A-63162 has immunosuppressive activity that may be due to inhibition of LTB4 production or to direct inhibitory actions of A-63162 on IL-2 and IL-6 synthesis.

In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma.

“…IL-6 is a proinflammatory cytokine produced by a variety of cells including monocytes. macrophages, fibroblasts, vascular endothelial cells, keratinocytes, T cells (reviewed in reference 8), mast cells (16) and epithelial cells (17). IL-6 is involved in the final differentiation of B cells into immunoglobulin secreting cells and enhances IL-4-induced IgE synthesis by B cells (reviewed in reference 18).…”

PLIP, a Novel Splice Variant of Tip60, Interacts with Group IV Cytosolic Phospholipase A2, Induces Apoptosis, and Potentiates Prostaglandin Production

“…Positive colonies were grown up in TrpϪ, glucose-containing medium, and isolated prey plasmids were rescued using the method of Hoffman and Winston (34) and electroporated into KC8 strains of Escherichia coli. PLIP cDNA was cloned into pBluescript and pMT 3 and amplified in XL-1 Blue strains of E. coli for sequencing and transfection experiments. DNA was sequenced completely on both strands by using customized oligonucleotides and standard techniques (5).…”

“…One hundred microliters of sample or standard was vortex mixed with 500 l of anti-PGE 2 antibody and incubated at 4°C for 30 min. 3 H-PGE 2 (New England Nuclear) was added for 1 h at 4°C followed by 200 l of dextran-coated charcoal suspension. Samples were centrifuged at 2,000 ϫ g for 5 min, and radioactivity in supernatants was determined.…”

“…This nuclear localization may be critical for physiological and pathophysiological actions of cPLA 2 . Arachidonic acid-metabolizing enzymes, such as prostaglandin H 2 synthase-1 and -2 (COX-1 and -2) (70) and 5-lipoxygenase (77,78), are localized on the nuclear membrane, and eicosanoids have been found to regulate transcription (3,7,8,24). cPLA 2 inhibitors result in reduced levels of group IIA secretory PLA 2 mRNA (46), and cPLA 2 expression has been correlated with COX-2 mRNA expression (2).…”

Inhibition of leukotriene formation and IL-8 release by the PAF-receptor antagonist SM-12502

“…In this regard, TNF-gene expression is increased by LT~34 (36). Atluru et al (37) have shown that inhibition of leukotriene biosynthesis suppressed IL-2 or IL-6 gene expression. Furthermore, it was demonstrated that exogeneous LTB 4 increased IL-6 biosynthesis (38).…”