RANTES (regulated on activation normal T cell expressed) has been found at elevated levels in
biological fluids from patients with a wide range of allergic and
autoimmune diseases and is able to attract several subtypes of leukocytes including eosinophils and monocytes into inflamed tissue. Amino-terminal modifications of
RANTES produce receptor antagonists which are candidates for blocking this cellular recruitment.
Met-RANTES has been shown to modulate
inflammation in vivo, while
AOP-RANTES is a potent inhibitor of R5 human immunodeficiency virus type 1 (HIV-1) strains and has been shown to down-modulate CCR5 and prevent recycling of the receptor. We have studied the effect of
AOP-RANTES in eosinophil activation and have found that it is able to efficiently elicit eosinophil effector functions through CCR3, as measured by the release of
reactive oxygen species and
calcium mobilization, whereas
Met-RANTES is inactive in these assays.
AOP-RANTES is found to inhibit CCR3-mediated HIV-1
infection with moderate potency, in contrast to its potent inhibition of CCR5-mediated HIV-1
infection. Furthermore, we have investigated the abilities of these modified
proteins to down-modulate CCR1 and CCR3 from the surface of monocytes and eosinophils. We show here that
AOP-RANTES is much less effective than
RANTES in down-modulation of CCR1. Surprisingly, recycling of CCR1 was minimal after incubation with
RANTES while there was complete recycling with
AOP-RANTES. In the case of CCR3, no significant difference was found between
RANTES and
AOP-RANTES in down-modulation and recycling. It therefore appears that trafficking of
RANTES receptors follows different patterns, which opens up potential new targets for therapeutic intervention.