XXXX -independent protein kinase Cs mediate heterologous desensitization of leukocyte chemokine receptors by opioid receptors.

@entity4545 @entity9295 @entity7131 @entity2842 @entity11616 @entity460 @entity141 @entity10557
Heterologous desensitization of chemokine receptors by opioids has been considered to contribute to their immunosuppressive effects. Previous studies show that @entity4545 , an endogenous opioid, down-regulates chemotaxis of selected chemokine receptors via phosphorylation. In the present study, we further investigated the molecular mechanism of such cross-regulation. Our data showed that preincubation with @entity4545 inhibited both @entity10557 -mediated chemotaxis and @entity141 flux of monocytes in a dose-dependent manner. The inhibitory effects were maximal using nanomolar concentrations of activating chemokines, a concentration found in physiological conditions. A decrease both in chemokine receptor affinity and in coupling efficiency between receptors and G protein were observed, which directly contributed to the desensitization effects. However, comparing with chemokines such as @entity10557 and @entity2842 , opioids did not elicit a @entity460 flux, failed to induce @entity10557 receptors internalization, and mediated a less potent heterologous desensitization. We hypothesized that these differences might originate from the involvement of different @entity7131 ( @entity7131 ) isotypes. In our studies, opioid-mediated down-regulation of @entity10557 receptors could be blocked by the general @entity7131 inhibitor @entity11616 , but not by the @entity460 -dependent classic @entity7131 inhibitor @entity9295 . Western blotting analysis and immunofluorescent staining further showed that only @entity460 -independent PKCs were activated upon opioid stimulation. Thus, opioids achieve desensitization of chemokine receptors via a unique pathway, involving only @entity460 -independent @entity7131 isotypes.
