Beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals.
The present study investigates the role of the HIV-suppressive beta-chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1 and RANTES in activation-induced cell death (AICD). A pool of these beta-chemokines reduced anti-CD3-induced apoptosis of T cell blasts from healthy blood donors in a dose-dependent manner. Although the pooled beta-chemokines were more effective, the inhibitory effect could also be mediated by each of the individual chemokines and was blocked by neutralizing anti-chemokine antibodies. The beta-chemokines also inhibited pokeweed mitogen/staphylococcal enterotoxin B-induced T lymphocyte apoptosis in 33/49 HIV-infected (HIV+) individuals. This anti-apoptotic effect was not correlated with the patients' CD4 T cell counts. beta-chemokines did not lead to altered secretion of IL-2, IL-4, IFN-gamma or IL-10 in response to activation stimuli in either normal T cell blasts or peripheral blood mononuclear cells from HIV+ individuals. Co-incubation with beta-chemokines did not inhibit anti-CD3-induced expression of cell surface Fas ligand, nor did it alter levels of the death receptor Fas or Bcl-2 in T cell blasts, suggesting that the beta-chemokines are blocking AICD downstream of Fas. These observations indicate that beta-chemokines may play a novel role as modulators of AICD, in addition to their known role as chemoattractants and inhibitors of HIV replication.
Pinto
L A
LA
Experimental Immunology Branch, National Instititutes of Health, National Cancer Institute, Bethesda, USA.
Williams
M S
MS
Dolan
M J
MJ
Henkart
P A
PA
Shearer
G M
GM
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D053222:Fas Ligand Protein; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D011043:Pokeweed Mitogens / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013211:Staphylococcus aureus; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004768:Enterotoxins; D053222:Fas Ligand Protein; D007371:Interferon-gamma; D016753:Interleukin-10; D007376:Interleukin-2; D015847:Interleukin-4; D037181:Lectins, C-Type; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D011043:Pokeweed Mitogens; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D000099192:CD69 Antigens; C505661:FASLG protein, human; C031818:enterotoxin B, staphylococcal