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  • Title: Staurosporine restores signaling and inhibits interleukin-8-induced chemotactic desensitization.
    Author: Johnston JA, Ferris DK, Wang JM, Longo DL, Oppenheim JJ, Kelvin DJ.
    Journal: Eur J Immunol; 1994 Oct; 24(10):2556-62. PubMed ID: 7925583.
    Abstract:
    Interleukin 8 (IL-8) is a chemotactic cytokine (chemokine) that plays a key role in the accumulation and activation of neutrophils at inflammatory sites. In this report we demonstrate that homologous chemotactic desensitization occurs upon pretreatment of neutrophils with IL-8 or N-formyl-methionyl-leucyl-phenylalanine (FMLP) and results in the inhibition of neutrophil chemotaxis upon subsequent challenge with the same ligand. This homologous chemotactic desensitization could be prevented by pretreating the neutrophils with the protein kinase inhibitor staurosporine, indicating that protein kinases may play an essential role. The attenuation of homologous desensitization by staurosporine restored chemotaxis but was not associated with a change in IL-8 receptor expression, affinity or the rate of ligand internalization, indicating that homologous desensitization does not alter ligand-receptor interaction. Using two-dimensional analysis we have shown that IL-8 induced a rapid serine/threonine phosphorylation of a number of neutrophil substrates the most prominent being phosphoprotein 39 (pp39), extracellular signal-related kinase-1, pp55 and pp66. Prior desensitization of neutrophils with IL-8 blocked all subsequent phosphorylation upon rechallenge with IL-8. However, the desensitization was specific for IL-8 since normal phosphorylation of identical substrates was observed in response to FMLP. When neutrophils were pretreated with staurosporine, prior to desensitization, phosphorylation of pp39 was observed upon restimulation with IL-8. Further study revealed that pp55 and pp66 were not phosphorylated in the presence of staurosporine. Thus, homologous desensitization of neutrophils in response to IL-8 does not result from changes in receptor expression, but rather from a staurosporine-sensitive inactivation of subsequent signal transduction. This desensitization is selective since the cells are able to respond to other ligands.
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