Autocrine regulation of interleukin-8 production in human monocytes

Interleukin (IL)-8 is a C-X-C chemokine that plays an important role in acu te 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 b lood mononuclear cells (MNCs). Sepharose-immobilized IL-8 stimulated a seve nfold increase in IL-8 production within 2 h. IL-8 induced the expression o f its own message, and IL-8 biosynthesis was inhibited by cycloheximide and actinomycin D, indicating de novo RNA and protein synthesis. In contrast t o 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-alpha (MGSA/GR O alpha), which binds CXCR2 but not CXCR1, was unable to either stimulate I L-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-in duced IL-8 biosynthesis was suggested by the ability of PD-98059, an inhibi tor of MAPK kinase, to block this function. Furthermore, IL-8 induced a sig nificant increase in extracellular signal-regulated kinase 2 phosphorylatio n, whereas MGSA/GRO alpha was much less effective. These findings support t he role of IL-8 as an autocrine regulator of IL-8 production and suggest th at this function is mediated by CXCR1 through activation of MAPK.