Altered hepatic lymphocyte subpopulations in... : Hepatology (original) (raw)
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Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: Potential mechanism for sensitization to liver damage
Guebre-Xabier, Mimi1, †; Yang, ShiQi2; Lin, Hui Zhi2; Schwenk, Robert1; Krzych, Ursula1; Diehl, Anna Mae M.D.*,2
1Department of Immunology, Walter Reed Army Institute for Research, Washington, DC
2Department of Medicine, Johns Hopkins University, Baltimore, MD
E-mail:[email protected]
*Address reprint requests to: Ross 912, The Johns Hopkins University School of Medicine, 720 Rutland Street, Baltimore, MD 21205. fax: (410) 955-9677.
†Drs. Guebre-Xabier and Schwenk made an equal contribution to the work, and either could be considered as first author
Received October 12, 1999; Accepted December 27, 1999; previously published online December 30, 2003
Abstract
Although obesity-related fatty livers are vulnerable to damage from endotoxin, the mechanisms involved remain obscure. The purpose of this study was to determine if immunologic priming might be involved by determining if fatty livers resemble normal livers that have been sensitized to endotoxin damage by Propionibacterium acnes infection. The latter induces interleukin (IL)-12 and -18, causing a selective reduction of CD4+NK T cells, diminished IL-4 production, deficient production of T-helper type 2 (Th-2) cytokines (e.g., IL-10), and excessive production of Th-1 cytokines (e.g., interferon gamma [IFN-γ]). Liver and spleen lymphocyte populations and hepatic cytokine production were compared in genetically obese, ob/ob mice (a model for obesity-related fatty liver) and lean mice. Obese mice have a selective reduction of hepatic CD4+NK T cells. Serum IL-18 is also increased basally, and the hepatic mRNA levels of IL-18 and -12 are greater after endotoxin challenge. Thus, up-regulation of IL-18 and IL-12 in fatty livers may reduce hepatic CD4+NK T cells. In addition, mononuclear cells from fatty livers have decreased expression of the adhesion molecule, leukocyte factor antigen-1 (LFA-1), which is necessary for the hepatic accumulation of CD4+NK T cells. Consistent with reduced numbers of hepatic CD4+NK T cells, mononuclear cells from fatty livers produce less IL-4. Furthermore, after endotoxin treatment, hepatic induction of IL-10 is inhibited, while that of IFN-γ is enhanced. Thus, fatty livers have inherent immunologic alterations that may predispose them to damage from endotoxin and other insults that induce a proinflammatory cytokine response.
© 2000 John Wiley & Sons, Ltd.