Thymic stromal lymphopoietin and interleukin-4 mediate the pathogenesis of halothane-induced liver injury in mice.
Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease has remained largely unknown. In this regard, it was recently shown that eosinophils played a pathogenic role in a mouse model of halothane-induced liver injury (HILI). However, the signaling events that drove hepatic expression of eosinophil-associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating hepatic epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) and type 2 immunity, in particular, interleukin-4 (IL-4) production, in mediating hepatic eosinophilia and injury during HILI. TSLP was constitutively expressed by mouse hepatocytes and increased during HILI. Moreover, the severity of HILI was reduced in mice deficient in either the TSLP receptor (TSLPR) or IL-4 and was accompanied by decreases in serum levels of eotaxins and hepatic eosinophilia. Similarly, concanavalin A-induced liver injury, where type 2 cytokines and eosinophils play a significant role in its pathogenesis, was also reduced in TSLPR-deficient mice. Studies in vitro revealed that mouse and human hepatocytes produce TSLP and eotaxins in response to treatment with combinations of IL-4 and proinflammatory cytokines IL-1β and tumor necrosis factor alpha.


CONCLUSIONS
This report provides the first evidence implicating roles for hepatic TSLP signaling, type 2 immunity, and eosinophilia in mediating liver injury caused by a drug.
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
William R
WR
Proctor
Mala
M
Chakraborty
Aaron M
AM
Fullerton
Midhun C
MC
Korrapati
Pauline M
PM
Ryan
Kenrick
K
Semple
Jeffrey C
JC
Morrison
Julia D
JD
Berkson
Lynette S
LS
Chea
Qian
Q
Yang
Albert P
AP
Li
Rosanne
R
Spolski
Erin E
EE
West
Yrina
Y
Rochman
Warren J
WJ
Leonard
Mohammed
M
Bourdi
Lance R
LR
Pohl
D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003208:Concanavalin A; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006221:Halothane / Q000009:adverse effects*; D006520:Hepatitis, Animal / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D000094632:Thymic Stromal Lymphopoietin
D018685:Anesthetics, Inhalation; D016207:Cytokines; D003208:Concanavalin A; D015847:Interleukin-4; D006221:Halothane; D000094632:Thymic Stromal Lymphopoietin