Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: Possible role of Akt and IRAK-M

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. 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. 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. 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.