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PMID: 10681432 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 5 ·2000-02-29 ·Pages 2367-72

Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G

Abstract

The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.

MeSH Terms
ADP Ribose Transferases Animals Bacterial Toxins Chemical and Drug Induced Liver Injury/immunology,metabolism Concanavalin A/toxicity Exotoxins/toxicity Female Interleukin-18/immunology,metabolism Leptin/immunology,pharmacology Liver/drug effects Mice Mice, Inbred C57BL Mice, Knockout Mice, Obese T-Lymphocytes/immunology Tumor Necrosis Factor-alpha/immunology,metabolism Virulence Factors
Chemicals
Bacterial Toxins Exotoxins Interleukin-18 Leptin Tumor Necrosis Factor-alpha Virulence Factors Concanavalin A ADP Ribose Transferases toxA protein, Pseudomonas aeruginosa
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Faggioni R
Metabolism Section, Department of Veteran Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
Jones-Carson J
Reed D A
Dinarello C A
Feingold K R
Grunfeld C
Fantuzzi G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.040561297
Published
2000-02-29
Pages
2367-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15807
Subset
IM
Grants
NIAID NIH HHS · R01 AI015614 · United States
NIAID NIH HHS · R56 AI015614 · United States
NIAID NIH HHS · AI-15614 · United States
NIDDK NIH HHS · DK-49448 · United States
External Links
PubMed source DOI: 10.1073/pnas.040561297 PMC Full Text View journal details
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