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Platelet Factor 4 (CXC Chemokine Ligand 4) Differentially Regulates Respiratory Burst, Survival, and Cytokine Expression of Human Monocytes by Using Distinct Signaling Pathways¹

Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany

Platelet factor 4 (PF4; CXCL4) is an abundant platelet -granule CXC chemokine with unique functions. Although lacking a chemotactic activity, PF4 initiates a signal transduction cascade in human monocytes leading to the induction of a broad spectrum of acute and delayed functions including phagocytosis, respiratory burst, survival, and the secretion of cytokines. Surprisingly, although these monocyte functions are well defined, only very limited information exists on the specific signaling pathways that are involved in the regulation of these biological responses. By using specific inhibitors and direct phosphorylation/activation studies, we show in the present study that PF4-mediated respiratory burst is dependent on a very rapid activation of PI3K, Syk, and p38 MAPK. Moreover, monocyte survival and differentiation instead is controlled by a delayed activation of Erk, with an activity peak after 6 h of stimulation. The inhibition of Erk completely reverted PF4-mediated protection against apoptosis. Finally, even though JNK is rapidly activated in PF4-treated monocytes, it is dispensable for the regulation of survival and respiratory burst. However, PF4-induced up-regulation of chemokine and cytokine mRNA and protein requires a sustained activation of JNK and Erk. Taken together, PF4-stimulated immediate monocyte functions (oxygen radical formation) are regulated by p38 MAPK, Syk, and PI3K, whereas delayed functions (survival and cytokine expression) are controlled by Erk and JNK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 415, Projekt B6.

² Address correspondence and reprint requests to Dr. Brigitte Kasper, Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22a, 23845 Borstel, Germany. E-mail address: bkasper{at}fz-borstel.de

³ Abbreviations used in this paper: PF4, platelet factor 4; ROS, reactive oxygen species; MBP, myelin basic protein; pMBP, phosphorylated MBP; PI, propidium iodide; RQ-PCR, real-time quantitative PCR; b2M, ₂-microglobulin.

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