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1 Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612; and 2 Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
Interleukin (IL)-8 is a C-X-C chemokine that plays an important
role in acute inflammation through its G protein-coupled receptors
CXCR1 and CXCR2. In this study, we investigated the role of IL-8 as an
autocrine regulator of IL-8 production and the signaling mechanisms
involved in human peripheral blood mononuclear cells (MNCs).
Sepharose-immobilized IL-8 stimulated a sevenfold increase in IL-8
production within 2 h. IL-8 induced the expression of its own
message, and IL-8 biosynthesis was inhibited by cycloheximide and
actinomycin D, indicating de novo RNA and protein synthesis. In
contrast to MNCs, polymorphonuclear neutrophils did not respond to the
immobilized IL-8 with IL-8 production despite cell surface expression
of CXCR1 and CXCR2. Melanoma
growth-stimulatory activity/growth-related protein-
(MGSA/GRO
), which binds CXCR2 but not CXCR1, was unable to
either stimulate IL-8 secretion in MNCs or desensitize these cells to
respond to immobilized IL-8. The involvement of mitogen-activated protein kinase (MAPK) in IL-8-induced IL-8 biosynthesis was suggested by the ability of PD-98059, an inhibitor of MAPK kinase, to block this
function. Furthermore, IL-8 induced a significant increase in
extracellular signal-regulated kinase 2 phosphorylation, whereas MGSA/GRO
was much less effective. These findings support the role of
IL-8 as an autocrine regulator of IL-8 production and suggest that this
function is mediated by CXCR1 through activation of MAPK.
cytokines; chemokines; inflammation; monocytes
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