CHEMOKINES OF THE ALPHA,BETA-SUBCLASS INHIBIT HUMAN BASOPHILS RESPONSIVENESS TO MONOCYTE CHEMOTACTIC AND ACTIVATING FACTOR MONOCYTE CHEMOATTRACTANT PROTEIN-1

Monocyte chemotactic and activating factor (MCAF) is the most potent c ytokine that activates basophils to release histamine. The response of human basophils to either simultaneous or sequential addition of the chemokines RANTES, macrophage inflammatory protein (MIP)-1 alpha, MIP- 1 beta platelet factor (PF)4, connective tissue activating peptide III (CTAP-III), interleukin (IL)-8, and inflammatory protein (IP)-10 on M CAF-induced histamine release was studied Simultaneous addition of MCA F and any of the chemokines studied evoked an augmented response as me asured by histamine release, whereas preincubation of leukocytes or pu rified basophils (80%) with these chemokines decreased MCAF-incduced h istamine release in a dose-dependent manner. Histamine release by anti -IgE remained unchanged. When tested at 5 X 10(-9) mol/L, the decrease in histamine release by RANTES was 69.2% +/- 3.5%, by MIP-1 alpha 48. 8% +/- 3.1%, by MIP-1 beta 42.9% +/- 3.1%, by PF4 56.5% +/- 2.9%, by I L-8 41.2% +/- 2.2 by CTAP III 27% +/- 4.4%, and by IP-10 15.3% +/- 2.6 %. The peak inhibition of histamine release by the chemokines was reac hed within 10 minutes of preincubation with basophils and remained unc hanged thereafter Washing basophils after preincubation with chemokine s abolished the inhibition, with the exception of desensitization by l ow concentrations of MCAF. With the exclusion of MCAF and RANTES, none of the chemokines (at the concentration range of 5 X 10(-8) to 5 X 10 (-11)) induced significant (>10% above spontaneous) histamine release from basophils. Preincubation of basophils with C5a (5 x 10(-10) mol/L ) did not affect histamine release, whereas preincubation with granulo cyte-macrophage colony-stimulating factor (10 ng/ml) or IL-5 (10 ng/ml ) enhanced MCAF-induced histamine release by 121.8% +/- 10.1% and 108% +/- 20.8%, respectively. We have therefore characterized RANTES, MIP- 1 alpha, MIP-1 beta CTAP III, PF4, IL-8, and IP-10 as inhibitors of MC AF-induced histamine release. Although the results are consistent with receptor blockade, the alpha and beta chemokines appear to interact w ith separate receptors linked to G proteins; thus a mechanism of recep tor class desensitization is proposed Interaction of this group of cyt okines at the site of allergic inflammation may modulate a function of basophils to initiate, augment, or inhibit histamine release.