We read with interest the article by Kerfoot et al. describing a 1.8-fold expansion of circulating monocytes activated to tumor necrosis factor ␣ (TNF-␣) production 10 days after bile-duct resection in mice, and the accompanying editorial. 1,2 Notably, activated monocytes are recruited into brain tissue by abnormally activated endothelial cells with subsequent activation of resident macrophages to TNF-␣ production. The authors hypothesize that the TNF-␣ delivered to the brain might contribute to the sickness behavior of cholestasis. We would like to point out that the key finding of Kerfoot's study, i.e., an expansion in peripheral blood of TNF-␣-secreting monocytes capable of infiltrating somatic tissues, 3 is a characteristic shared by human and experimental cirrhosis, 4,5 a disease in which fatigue is a prominent feature. 6 In rats with CCl 4 cirrhosis and patients with cirrhosis, numbers of TNF-␣secreting monocytes in peripheral blood increase by 45-and 26fold, respectively. The marked increase in TNF-␣-secreting monocytes is accompanied by polarization of the T-helper cell compartment toward a Th1 pattern of activation with increased interferon-␥ production. 5 Expansion in the peripheral blood of these abnormally activated immune cells leads to increased serum levels of proinflammatory cytokines, including TNF-␣, interferon-␥, interleukin (IL)-1, and IL-6. 5,7,8 Experimental and clinical data have shown that immune cell activation initiates in the mesenteric lymph nodes and is promoted by gut bacterial translocation. 4,5,8 Thereafter, the activated monocytes and T lymphocytes gain access to the peripheral blood by recirculation. Thus, the notion proposed in Kerfoot's article and the accompanying editorial would need to be explored in cirrhosis to establish the infiltration of brain tissue by activated monocyte/macrophages and their potential role in the pathogenesis of associated fatigue. In addition, we would like to draw attention to the possibility that the marked systemic inflammation demonstrated in cirrhosis may also be involved in the pathogenesis of fatigue, a proposal based on a combination of several known mechanisms including: (1) the combined direct effects on the brain of circulating pro-inflammatory cytokines elevated in cirrhosis, such as TNF-␣, interferon-␥, IL-1, and IL-6; and (2) the direct skeletal muscle disturbance with increased proteolysis of muscle fibers provoked by TNF-␣ alone, or in combination with other cytokines such as interferon-␥. 9 Immunological mechanisms underlie the pathogenesis of cholestasis and liver cirrhosis, and their complications including fatigue. [1][2][3][4][5]8,10 Their unsuspected role in liver diseases, that were not previously considered immune-mediated, points to immune components as novel targets in translational medicine efforts directed to broaden therapeutic options.