Administration of ricin induces a severe inflammatory response via nonredundant stimulation of ERK, JNK, and p38 MAPK and provides a mouse model of hemolytic uremic syndrome

Veselina Korcheva, John Wong, Christopher Corless, Mihail Iordanov, Bruce Magun

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Recent interest in the health consequences of ricin as a weapon of terrorism has led us to investigate the effects of ricin on cells in vitro and in mice. Our previous studies showed that depurination of the 28S rRNA by ricin results in the inhibition of translation and the coordinate activation of the stress-activated protein kinases JNK and p38 MAPK. In RAW 264.7 macrophages, ricin induced the activation of ERK, JNK, and p38 MAPK, the accumulation of mRNA encoding tumor necrosis factor (TNF)-α, interleukin (IL)-1, the transcription factors c-Fos, c-Jun, and EGR1, and the appearance of TNF-α protein in the culture medium. Using specific inhibitors of MAPKs, we demonstrated the nonredundant roles of the individual MAPKs in mediating proinflammatory gene activation in response to ricin. Similarly, the intravenous administration of ricin to mice led to the activation of ERK, JNK, and p38 MAPK in the kidneys, and increases in plasma-borne TNF-α, IL-1β, and IL-6. Ricin-injected mice developed the hallmarks of hemolytic uremic syndrome, including thrombotic microangiopathy, hemolytic anemia, thrombocytopenia, and acute renal failure. Microarray analyses demonstrated a massive proinflammatory transcriptional response in the kidneys, coincidental with the symptoms of hemolytic uremic syndrome. Therapeutic management of the inflammatory response may affect the outcome of intoxication by ricin.

Original languageEnglish (US)
Pages (from-to)323-339
Number of pages17
JournalAmerican Journal of Pathology
Volume166
Issue number1
Publication statusPublished - Jan 2005

    Fingerprint

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this