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Role of MAP Kinases and PI 3K‐Akt on the cytokine inflammatory profile of peritoneal macrophages from the ascites of cirrhotic patients
Author(s) -
TapiaAbellán Ana,
RuizAlcaraz Antonio J.,
HernándezCaselles Trinidad,
Such José,
Francés Rubén,
GarcíaPeñarrubia Pilar,
MartínezEsparza María
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12072
Subject(s) - mapk/erk pathway , pi3k/akt/mtor pathway , protein kinase b , cytokine , proinflammatory cytokine , p38 mitogen activated protein kinases , monocyte , kinase , tumor necrosis factor alpha , pharmacology , inflammation , chemistry , medicine , biology , immunology , phosphorylation , signal transduction , microbiology and biotechnology
Aims Several new approaches targeting inflammation associated with different diseases are in clinical development. Objective To explore the role played by MAPK and PI 3K‐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. Methods M‐ DM were isolated from the ascites of cirrhotic patients and stimulated in vitro with LPS and heat‐killed C andida albicans in the presence or absence of the inhibitors for MEK 1, p38 MAPK , JNK and PI 3K. The MAPK phosphorylation levels were determined by Western Blot. Cell culture supernatants were assayed by ELISA for TNF ‐α, IL ‐6 and IL ‐10. Results 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 PI 3K 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 PI 3K. Finally, inhibition of PI 3K almost completely suppressed the secretion of IL ‐10 in stimulated M‐ DM . Conclusions 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 PI 3K‐Akt pathway in the modulation of IL ‐10‐mediated anti‐inflammatory function.