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.
Experimental Immunology Branch, National Instititutes of Health, National Cancer Institute, Bethesda, USA.
L A
LA
Pinto
M S
MS
Williams
M J
MJ
Dolan
P A
PA
Henkart
G M
GM
Shearer
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