IP-10 protects while MIP-2 promotes experimental anesthetic hapten - induced hepatitis.
MIP-2 and IFN-gamma inducible protein-10 (IP-10) and their respective receptors, CXCR2 and CXCR3, modulate tissue inflammation by recruiting neutrophils or T cells from the spleen or bone marrow. Yet, how these chemokines modulate diseases such as immune-mediated drug-induced liver injury (DILI) is essentially unknown. To investigate how chemokines modulate experimental DILI in our model we used susceptible BALB/c (WT) and IL-4-/- (KO) mice that develop significantly reduced hepatitis and splenic T cell priming to anesthetic haptens and self proteins following TFA-S100 immunizations. We detected CXCR2+ splenic granulocytes in all mice two weeks following immunizations; by three weeks, MIP-2 levels (p<0.001) and GR1+ cells were elevated in WT livers, suggesting MIP-2-recruited granulocytes. Elevated splenic CXCR3+CD4+T cells were identified after two weeks in KO mice indicating elevated IP-10 levels which were confirmed during T cell priming. This result suggested that IP-10 reduced T cell priming to critical DILI antigens. Increased T cell proliferation following co-culture of TFA-S100-primed WT splenocytes with anti-IP-10 (p<0.05) confirmed that IP-10 reduced T cell priming to CYP2E1 and TFA. We propose that MIP-2 promotes and IP-10 protects against the development of hepatitis and T cell priming in this murine model.
Njoku
Dolores B
DB
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USA. dnjoku1@jhmi.edu
Li
Zhaoxia
Z
Mellerson
Jenelle L
JL
Sharma
Rajni
R
Talor
Monica V
MV
Barat
Nicole
N
Rose
Noel R
NR
D000777:Anesthetics / Q000009:adverse effects / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D054370:Chemokine CXCL9 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000276:immunology / Q000378:metabolism; D005260:Female; D006241:Haptens / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018448:Models, Immunological; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014269:Trifluoroacetic Acid / Q000276:immunology
D000777:Anesthetics; D000906:Antibodies; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D054370:Chemokine CXCL9; C404915:Cxcl2 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D006241:Haptens; D054367:Receptors, CXCR3; D023063:Receptors, Interleukin-8B; D015847:Interleukin-4; D014269:Trifluoroacetic Acid; D019392:Cytochrome P-450 CYP2E1