3.3.6. Ricin B-Chain-Induced Apoptosis

Studies carried on U937 cells have demonstrated that the interaction of ricin B-chain with membrane glycoproteins and glycolipids may trigger signaling events leading to apoptosis [33]. This lectin activity-dependent mechanism was distinct from apoptosis signaling pathways induced by ricin A-chain. It has been demonstrated that carboxymethylated-(CM-) ricin B-chain was responsible for DNA fragmentation and typical apoptotic nuclear morphological changes, which were very similar to those observed in ricin-treated cells [33]. CM-ricin B-chain failed to inhibit protein synthesis in U937 cells. Thus, these experiments support the hypothesis that ricin-induced apoptosis or at least some of the apoptotic pathways are independent and not correlated with protein synthesis inhibition, at least in U937 cells. Recently published results have also shown that ricin-induced apoptosis is not solely attributed to the A-chain [243]. The intact heterodimeric ricin and ricin chains were injected into rats in order to study ricin-induced apoptosis in liver, which is a major site of in vivo ricin uptake and cytotoxicity [262]. It has been demonstrated that ricin was responsible for the intrinsic apoptosis pathway since increased cytochrome c content, activation of caspase-9 and caspase-3, and enrichment of DNA fragments in the cytosol were observed [243]. These authors observed also the B-chain in the cytosol and reported that it caused cytochrome c release from mitochondria in vivo and in vitro. These results sugges<sup>t</sup> that a direct interaction of ricin B-chain with the mitochondrial outer membrane can be involved in ricin-induced apoptosis. The involvement of recombinant RTB in macrophage activation has also been studied [263]. It was demonstrated that RTB stimulated inducible nitric oxide (NO) synthase (iNOS) and TNF-α and IL-6 expression, which are involved in the activation of protein tyrosine kinase, NF-κB and JAK-STAT signaling.
