title: Immunoregulation by low density lipoproteins in man. Inhibition of mitogen-induced T lymphocyte proliferation by interference with transferrin metabolism.
abstract: Human low density lipoprotein (LDL, d = 1.020-1.050 g/ml) inhibits mitogen-stimulated T lymphocyte DNA synthesis. Because both LDL and transferrin bind to specific cell surface receptors and enter cells by the similar means of receptor-mediated endocytosis, and because transferrin is necessary for lymphocyte DNA synthesis, we investigated the possibility that LDL may inhibit mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL inhibited mitogen-stimulated lymphocyte [3H]thymidine incorporation in a concentration-dependent manner. The degree of inhibition was most marked in serum-free cultures, but was also observed in serum-containing cultures. The addition of transferrin not only augmented mitogen-induced lymphocyte [3H]thymidine incorporation in serum-free medium but also completely reversed the inhibitory effect of LDL in both serum-free and serum-containing media. Similar results were obtained when lymphocyte proliferation was assayed by counting the number of cells in culture. Transferrin also reversed the inhibition of lymphocyte responses caused by very low density lipoproteins and by cholesterol. The ability of transferrin to reverse the inhibitory effect of lipoproteins was specific, in that native but not denatured transferrin was effective whereas a variety of other proteins were ineffective. These results indicate that LDL inhibits mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL only inhibited lymphocyte responses after a 48-h incubation if present from the initiation of the culture. By contrast, transferrin reversed inhibition when added after 24 h of the 48-h incubation. LDL did not inhibit lymphocyte responses by nonspecifically associating with transferrin. In addition, the acquisition of specific lymphocyte transferrin receptors was not blocked by LDL. Moreover, transferrin did not prevent the binding and uptake of fluorescent-labeled LDL by activated lymphocytes. Furthermore, LDL did not prevent the binding of transferrin to its receptor. Finally, LDL inhibition did not require specific high affinity cell surface receptors for cholesterol transport by LDL because similar inhibition and reversal by transferrin were observed with lymphocytes from a patient with homozygous familial hypercholesterolemia. Thus, LDL alters lymphocyte responses in a non-LDL receptor-mediated way by interfering with transferrin metabolism after specific binding of transferrin to receptors on activated lymphocytes.
mesh_terms: D000328:Adult; D002784:Cholesterol / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008074:Lipoproteins / Q000494:pharmacology; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D011973:Receptors, LDL; D011990:Receptors, Transferrin; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D010835:Phytohemagglutinins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D011990:Receptors, Transferrin; D014168:Transferrin; D002784:Cholesterol