Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M.
OBJECTIVE
In cirrhosis, tumor necrosis factor (TNF)-alpha overproduction is involved in both the systemic complications and progression of liver injury. Since monocytes from patients with advanced cirrhosis have an increase in lipopolysaccharide (LPS)-induced TNF-alpha production, we hypothesized that an upregulation of TNF-alpha production pathways and/or alteration of constitutive and inducible suppressor of TNF-alpha hyperproduction (protein kinase B (Akt) and interleukin-1 receptor-associated kinase (IRAK)-M, respectively) should be found in monocytes of these patients. Thus, we investigated ex vivo the signaling pathways of TNF-alpha production before and after LPS incubation in monocytes from noninfected Child-Pugh C patients with advanced cirrhosis and healthy subjects.


METHODS
TNF-alpha production, expressions of intracellular TNF-alpha, toll-like receptor-4 (TLR4), IkappaB-alpha, IRAK-1, IRAK-M, mitogen-activated protein (MAP) kinases and Akt activity were measured in monocytes.


RESULTS
Cirrhotic monocytes without LPS have less TLR4 expression, less IkappaB-alpha protein levels, more TNF-alpha expression, higher MAP kinase activities and decreased Akt activity than control monocytes. In cirrhotic monocytes, LPS-induced TNF-alpha hyperproduction and signaling upregulation were associated with a lack of IRAK-M induction.


CONCLUSIONS
Upregulated signaling pathways of the TNF-alpha production, decreased Akt activity and a lack of IRAK-M induction may be involved in the process of cirrhotic monocyte sensitization to produce TNF-alpha.
Tazi
Khalid A
KA
INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Hôpital Beaujon, Clichy, France. ktazi@bichat.inserm.fr
Quioc
Jean-Jacques
JJ
Saada
Véronique
V
Bezeaud
Annie
A
Lebrec
Didier
D
Moreau
Richard
R
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D014409:Tumor Necrosis Factor-alpha; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt