Pathophysiological Aspects of Proteases by Sajal Chakraborti & Naranjan S. Dhalla

Author:Sajal Chakraborti & Naranjan S. Dhalla
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

7 Artesunate and MMPs

During Plasmodium infection, the blood levels of TNF-α increase because of the activation of monocyte-macrophages, caused either by infected erythrocytes or parasite molecules, such as the malaria pigment hemozoin. As previously said, this induces an up-regulation of MMP-9 either in monocytes or macrophages with a following proteolytical effect not only on the ECM but also on precursors of inflammatory cytokines, amplifying the inflammatory response [36].

Artemisinin and its derivatives such as artemisone, artesunate, and dihydroartemisinin (DHA) can immunomodulate the host response, in fact, they inhibit the mRNA synthesis and the production of MMP-9 in human monocyte-like cells, after stimulation with hemozoin or TNF-α. Artesunate, artemisone, and DHA were capable to antagonize MMP-9 secretion as well as its expression, stimulated by hemozoin, up to 50%.

The derivatives significantly down-regulated both TNF-α-induced MMP-9 secretion and mRNA levels of the enzyme, in a more active way than hemozoin itself. Both hemozoin and TNF-α increased the transcription dependent on NF-kB by 11 and 7.7 fold, respectively. Artesunate, artemisone, and DHA inhibited the NF-kB driven transcription, induced by hemozoin, by 28, 34, and 49%, respectively. In a similar manner, the derivatives, differently from artemisinin, prevented TNF-α-induced NF-kB driven transcription by 47–51%. Furthermore, contrary to artemisinin, its derivatives such as artemisone, artesunate, and DHA, modulated MMP-9, and also other genes which depend on NF-kB, like TNF-α.

Artemisinins may turn off the inflammatory response of monocytes in vivo. Thus, the beneficial clinical effects of artemisinins for the treatment of malaria would include not only the direct anti-parasitic activities but also the ability to attenuate the inflammatory response, thus reducing the risk of progression to the more severe form of the disease, like the CM [129].

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