Article
Caspase-8 inhibition represses initial human monocyte activation in septic shock model
Author/s | Oliva Martín, María José
Sánchez Abarca, Luis Ignacio Rodhe, Johanna Carrillo Jiménez, Alejandro Vlachos, Pinelopi Herrera Carmona, Antonio José García Quintanilla, Alberto Caballero Velázquez, Teresa Venero Recio, José Luis |
Department | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular |
Publication Date | 2016 |
Deposit Date | 2017-02-22 |
Published in |
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Abstract | In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream ... In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source. |
Project ID. | info:eu-repo/grantAgreement/MINECO/SAF2012-39029
info:eu-repo/grantAgreement/MINECO/SAF2015-64171R P10-CTS-6494 |
Citation | Oliva Martín, M.J., Sánchez Abarca, L.I., Rodhe, J., Carrillo Jiménez, A., Vlachos, P., Herrera, A.J.,...,Venero Recio, J.L. (2016). Caspase-8 inhibition represses initial human monocyte activation in septic shock model. Oncotarget, 7 (25), 37456-37470. |
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