Abstract
Plasma apolipoprotein E (apoE) is a ligand for the cellular uptake of cholesterol-rich plasma lipoproteins. ApoE also inhibits mitogen-stimulated lymphocyte proliferation and gonadotropin-stimulated ovarian theca/interstitial cell androgen production. To address the mechanism(s) by which apoE is active and to understand its interaction with the target cells, we prepared and examined the inhibitory activity of a series of apoE synthetic peptides. ApoE peptides representing amino acid residues 93-112, 141-155, 161-171, 172-182, and 174-193 were not active in either bioassay. However, specific inhibition of both lymphocyte proliferation and ovarian androgen production was observed with a self-conjugate of peptide-(141-155). Furthermore, a synthesized dimeric peptide representing two repeats of sequence-(141-155) (i.e. (141-155)-(141-155] was active as well. In both bioassays, the inhibition observed was not a result of direct cell killing. Furthermore, these apoE peptides exhibited activities with characteristics that were shared with those of native apoE. The results indicate that amino acid residues 141-155 of apoE are responsible for the biological activity of apoE. Furthermore, the results suggest that dimers or multimers of native apoE may be a biologically important species.
Highlights
Plasma apolipoprotein E is a ligand for the lung, spleen, testes, ovary, and brain
In both systems, there is local and regulated productionof apolipoprotein E (apoE) by nearby accessorycells, the monocyte-derived macrophage (3) and the ovarian granulosa cell (11). Both of these accessory cells work in collabokilling. These apoE peptides exhibited ration with their respective apoE-sensitive effector cells to help regulate those of native apoE
It has been repeatedly uptake of PHA-stimulated lymphocytes (Fig. 1A) and the demonstrated that theinhibition by apoE of mitogen-stimuandrogen production of luteinizing hormone (LH)-stimulated ovarian theca/inter- lated lymphocyte proliferation is not readily reversible (9)
Summary
Inhibition of PHA-stimulated [3H]thymidine uptake, had no Peptides representing human apoE residues 93-112,141155, 161-171,172-182, and 174-193were synthesized and characterized (Table I).These different regions of apoE were selected because they representedthe putative LDL receptorbinding region and putative heparin-binding sites (1)or they were predicted to be antigenic determinants by the program effect on cell viability as assessed by trypan blue exclusion or on the retention of cell-associated LDH activity (Fig. 2). We prepared self-conjugates of synthetic stenedione production was inhibited at 20 pg/ml self-conjupeptides that represented three regions of another apolipo- gated apoE-(141-155), this same concentrationof peptide had protein, apoA-I, which does not have immunoregulatory ac- no effect on progesterone production (Fig. 3). Increasing was a true apoEfunctional mimic, i.e. it could mimic the amounts of this self-conjugate inhibited both the thymidine inhibition observed with intact apoE It has been repeatedly uptake of PHA-stimulated lymphocytes (Fig. 1A) and the demonstrated that theinhibition by apoE of mitogen-stimuandrogen production of LH-stimulated ovarian theca/inter- lated lymphocyte proliferation is not readily reversible (9). Self-conjugated peptide (3-4 pg/ml), which resulted in >90% this was not the case with the self-conjugate of Purity
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