ovalbumin and Chemical-and-Drug-Induced-Liver-Injury

Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo.. Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured.. Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice.. The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.

Topics: Allergens; Animals; Asthma; Chemical and Drug Induced Liver Injury; Female; Histamine Antagonists; Humans; Indoles; Interleukin-13; Kupffer Cells; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Tumor Necrosis Factor-alpha

V-set and Ig domain-containing 4 (VSIG4, CRIg, or Z39Ig), a newly identified B7-related cosignaling molecule, is a complement receptor and a coinhibitory ligand that negatively regulates T-cell immunity. Despite its exclusive expression on liver Kupffer cells (KCs) that play key roles in liver tolerance, the physiological role of VSIG4 in liver tolerance remains undefined. Mice lacking VSIG4 had poor survival rates and severe liver pathology in a concanavalin A (ConA)-induced hepatitis (CIH) model, which could be prevented by adoptive transfer of VSIG4(+) KCs. The absence of VSIG4 rendered endogenous liver T- and natural killer T (NKT)-cells more responsive to antigen-specific stimulation and impaired tolerance induction in those cells against their cognate antigens. T-cell costimulation with VSIG4.Ig suppressed Th1-, Th2-, and Th17-type cytokine production and arrested the cell cycle at the G(0) /G(1) phase but did not induce apoptosis in vitro. VSIG4-mediated tolerance induction and cell-cycle arrest were further supported by down-regulation of G(1) phase-specific Cdk2, Cdk4, and Cdk6, and up-regulation of tolerance-inducing p27(KIP-1) in VSIG4.Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged the survival of mice with established CIH.. Collectively, our results suggest that VSIG4(+) KCs play a critical role in the induction and maintenance of liver T- and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis.

Topics: Animals; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Coculture Techniques; Concanavalin A; Cytokines; Galactosylceramides; Hepatitis; Immune Tolerance; Immunoglobulin G; Kupffer Cells; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Ovalbumin; Receptors, Complement; Signal Transduction; T-Lymphocytes

Topics: Alloxan; Animals; Chemical and Drug Induced Liver Injury; Cholesterol; Fats; Glycerol; Kidney; Kidney Diseases; Lipase; Liver; Male; Nucleosides; Ovalbumin; Rats