Cirrhosis and Liver Failure
Role of MAP Kinases and PI3K-Akt on the cytokine inflammatory profile of peritoneal macrophages from the ascites of cirrhotic patients
Article first published online: 20 JAN 2013
© 2012 John Wiley & Sons A/S
Volume 33, Issue 4, pages 552–560, April 2013
How to Cite
Liver Int. 2013: 33: 552–560
- Issue published online: 12 MAR 2013
- Article first published online: 20 JAN 2013
- Accepted manuscript online: 21 NOV 2012 01:09AM EST
- Manuscript Accepted: 16 NOV 2012
- Manuscript Received: 6 AUG 2012
- Fundación Séneca, Comunidad Autónoma de la Región de Murcia. Grant Number: 12302/FPI/09
- MAP kinases;
Several new approaches targeting inflammation associated with different diseases are in clinical development.
To explore the role played by MAPK and PI3K-Akt pathways on the release of cytokines in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients to identify novel targets for pharmaceutical intervention to prevent hepatic damage.
M-DM were isolated from the ascites of cirrhotic patients and stimulated in vitro with LPS and heat-killed Candida albicans in the presence or absence of the inhibitors for MEK1, p38 MAPK, JNK and PI3K. The MAPK phosphorylation levels were determined by Western Blot. Cell culture supernatants were assayed by ELISA for TNF-α, IL-6 and IL-10.
The release of the pro-inflammatory cytokines IL-6 and TNF-α at baseline was more effectively reduced by the MAPK inhibitors, while the basal IL-10 anti-inflammatory cytokine secretion was only and strongly (90.3%) affected by the PI3K inhibitor. The incubation of peritoneal M-DM in the presence of LPS and C. albicans increased the release of IL-6, TNF-α and IL-10. LPS-induced pro-inflammatory cytokines secretion was more sensitive to MAPK inhibitors, whereas that induced by C. albicans was more susceptible to inhibition of PI3K. Finally, inhibition of PI3K almost completely suppressed the secretion of IL-10 in stimulated M-DM.
These results demonstrate that pro-inflammatory cytokines release in M-DM from this clinical setting strongly depends on the MAPK signalling pathways, differs depending on the microbial stimulus added and confirms the prominent role of the PI3K-Akt pathway in the modulation of IL-10-mediated anti-inflammatory function.