Ricin induces IL-8 secretion from human monocyte/macrophages by activating the p38 MAP kinase pathway.
Polymorphonuclear cell (PMN) infiltration is a hallmark of ricin-induced mucosal inflammation, yet the cellular processes involved in initiating this reaction remain undefined. In this study we report that ricin stimulates the human monocyte/macrophages cell line 28SC to secrete IL-8, a potent PMN chemoattractant. IL-8 release in response to ricin was both dose- and time-dependent. 28SC cells did not secrete IL-8 when exposed to formaldehyde-inactivated holotoxin or ricin B subunit. Furthermore, IL-8 induction could be blocked by brefeldin A, which inhibits ricin translocation into the cytosol. As predicted from the literature, we observed elevated levels of p38 mitogen activated protein kinase (MAPK), a post-transcriptional regulator of IL-8, in 28SC cells as early as 3h after ricin exposure. Treatment of 28SC cells with the pyridylimidizole analogue SB203580, a known inhibitor of p38 MAPK, suppressed ricin-mediated IL-8 release. We conclude that ricin stimulates human monocyte/macrophages to produce IL-8 by activation of the p38 MAPK pathway, raising the possibility that p38 MAPK inhibitors may potentially serve as therapeutic agents to suppress mucosal inflammation associated with ricin intoxication.
Gonzalez
Tessa V
TV
Department of Pediatrics, Harvard Medical School, and GI Cell Biology Laboratory, Children's Hospital Boston, Boston, MA 02115, USA.
Farrant
Stephanie A
SA
Mantis
Nicholas J
NJ
D020126:Brefeldin A / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006027:Glycosides / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D012276:Ricin / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D006027:Glycosides; D016209:Interleukin-8; D014315:Triterpenes; D020126:Brefeldin A; C001883:stichoposide; D012276:Ricin; D003513:Cycloheximide; D048051:p38 Mitogen-Activated Protein Kinases