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IL-2 Signaling in Human Monocytes Involves the Phosphorylation and Activation of p59^{hck 1}

Maria C. Bosco^*, Rafael E. Curiel, Arnold H. Zea, Maria G. Malabarba^§, John R. Ortaldo^¶ and Igor Espinoza-Delgado^2,

^* Laboratory of Molecular Biology, Giannina Gaslini Institute, Genova Quarto, Italy; Departments of Medicine and Microbiology and Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, LA 70112; and Laboratories of ^§ Immunoregulation and ^¶ Experimental Immunology, Cytokines Molecular Mechanisms Section, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702

The activating properties of IL-2 and the structure of the IL-2R on human monocytes are well characterized. However, relatively little is known about the biochemical mechanisms involved in IL-2 signal transduction in these cells. We investigated the role of protein tyrosine kinases (PTKs) in the activation of monocytes by IL-2. Incubation of monocytes with the PTK inhibitor herbimycin A (HA) resulted in the dose-dependent suppression of IL-2-induced monocyte tumoricidal activity. This inhibition was rather potent, as a concentration of HA as low as 0.5 µM caused a complete abrogation of cytolytic activity. Furthermore, HA markedly suppressed the ability of IL-2 to induce IL-1ß, TNF-, IL-6, and IL-8 mRNA expression and protein secretion by monocytes. Anti-phosphotyrosine immunoblotting demonstrated that IL-2 induced a rapid and time-dependent increase in tyrosine phosphorylation of several cellular proteins of molecular masses ranging from 35 to 180 kDa. Interestingly, IL-2 caused a significant up-regulation of the constitutive levels of hck PTK mRNA and protein relative to medium-treated cells as well as an increase in p59^hck tyrosine phosphorylation. Finally, we demonstrated by in vitro kinase assay that the specific activity of p59^hck PTK was also induced by IL-2 in monocytes. Thus, these data show that the activation of PTKs is required for the triggering of monocyte effector and secretory functions by IL-2 and strongly suggest that p59^hck is a key participant in IL-2 signaling in human monocytes.

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