Autocrine regulation of interleukin-8 production in human monocytes.
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-alpha (MGSA/GROalpha), 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/GROalpha 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.
Browning
D D
DD
Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Diehl
W C
WC
Hsu
M H
MH
Schraufstatter
I U
IU
Ye
R D
RD
D000911:Antibodies, Monoclonal; D019898:Autocrine Communication / Q000276:immunology*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000737:chemistry / Q000201:enzymology* / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000276:immunology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000032:analysis / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000032:analysis / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D011500:Protein Synthesis Inhibitors; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D003609:Dactinomycin; D003513:Cycloheximide; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one