Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants.
The biology of RANTES (regulated on activation normal T cell expressed) aggregation has been investigated using RANTES and disaggregated variants, enabling comparison of aggregated, tetrameric, and dimeric RANTES forms. Disaggregated variants retain their G(i)-type G protein-coupled receptor-mediated biological activities. A correlation between RANTES aggregation and cellular activation has been demonstrated. Aggregated RANTES, but not disaggregated RANTES, activates human T cells, monocytes, and neutrophils. Dimeric RANTES has lost its cellular activating activity, rendering it noninflammatory. Macrophage inflammatory protein 1alpha, macrophage inflammatory protein-1beta, and erythrocytes are potent natural antagonists of aggregated RANTES-induced cellular activation. There is a clear difference in the signaling properties of aggregated and disaggregated RANTES forms, separating the dual signaling pathways of RANTES and the enhancing and suppressive effects of RANTES on human immunodeficiency virus infection. Disaggregated RANTES will be a valuable tool to explore the biology of RANTES action in human immunodeficiency virus infection and in inflammatory disease.
Appay
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V
British Biotech Pharmaceuticals Ltd., Watlington Road, Oxford OX4 5LY, United Kingdom.
Brown
A
A
Cribbes
S
S
Randle
E
E
Czaplewski
L G
LG
D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004912:Erythrocytes / Q000502:physiology; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D019169:Jurkat Cells; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D054407:Chemokine CCL4; D018946:Chemokine CCL5; D046911:Macromolecular Substances; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D002118:Calcium