IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1

2004 ◽  
Vol 287 (5) ◽  
pp. G1044-G1052 ◽  
Author(s):  
Barbara Jaruga ◽  
Feng Hong ◽  
Won-Ho Kim ◽  
Bin Gao
Keyword(s):  
Endothelial Cells ◽  
T Cell ◽  
Adhesion Molecules ◽  
Kupffer Cells ◽  
Critical Role ◽  
Leukocyte Infiltration ◽  
Induced Expression ◽  
Hepatic Cells ◽  
Primary Mouse ◽  
Ifn Γ

We have previously shown that IFN-γ/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-γ/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-γ−/− and STAT1−/− mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-γ/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-γ (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-α chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-γ−/−, STAT1−/−, and IRF-1−/− mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-γ activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1−/− and IRF-1−/− hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-γ also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.

scholarly journals A critical role for the programmed death ligand 1 in fetomaternal tolerance

2005 ◽  
Vol 202 (2) ◽  
pp. 231-237 ◽  
Author(s):  
Indira Guleria ◽  
Arezou Khosroshahi ◽  
Mohammed Javeed Ansari ◽  
Antje Habicht ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Antibody Treatment ◽  
Programmed Death Ligand 1 ◽  
Fetal Survival ◽  
Programmed Death ◽  
Ifn Γ ◽  
Rag 1

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell– but not B cell–dependent because PDL1-specific antibody treatment caused fetal rejection in B cell–deficient but not in RAG-1–deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-γ–producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-γ levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.

scholarly journals CD16+ monocytes control T-cell subset development in immune thrombocytopenia

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3326-3335 ◽  
Author(s):  
Hui Zhong ◽  
Weili Bao ◽  
Xiaojuan Li ◽  
Allison Miller ◽  
Caroline Seery ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Thrombocytopenia ◽  
Critical Role ◽  
Cell Subset ◽  
Inhibitory Effect ◽  
Cell Polarization ◽  
T Cell Subsets ◽  
Monocyte Subset ◽  
Th Cells ◽  
Ifn Γ

Abstract Immune thrombocytopenia (ITP) results from decreased platelet production and accelerated platelet destruction. Impaired CD4+ regulatory T-cell (Treg) compartment and skewed Th1 and possibly Th17 responses have been described in ITP patients. The trigger for aberrant T-cell polarization remains unknown. Because monocytes have a critical role in development and polarization of T-cell subsets, we explored the contribution of monocyte subsets in control of Treg and Th development in patients with ITP. Unlike circulating classic CD14hiCD16− subpopulation, the CD16+ monocyte subset was expanded in ITP patients with low platelet counts on thrombopoietic agents and positively correlated with T-cell CD4+IFN-γ+ levels, but negatively with circulating CD4+CD25hiFoxp3+ and IL-17+ Th cells. Using a coculture model, we found that CD16+ ITP monocytes promoted the expansion of IFN-γ+CD4+ cells and concomitantly inhibited the proliferation of Tregs and IL-17+ Th cells. Th-1–polarizing cytokine IL-12, secreted after direct contact of patient T-cell and CD16+ monocytes, was responsible for the inhibitory effect on Treg and IL-17+CD4+ cell proliferation. Our findings are consistent with ITP CD16+ monocytes promoting Th1 development, which in turn negatively regulates IL-17 and Treg induction. This underscores the critical role of CD16+ monocytes in the generation of potentially pathogenic Th responses in ITP.

scholarly journals Immune-Mediated Protection from Measles Virus-Induced Central Nervous System Disease Is Noncytolytic and Gamma Interferon Dependent

2002 ◽  
Vol 76 (9) ◽  
pp. 4497-4506 ◽  
Author(s):  
Catherine E. Patterson ◽  
Diane M. P. Lawrence ◽  
Lisa A. Echols ◽  
Glenn F. Rall
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
T Cell ◽  
Neuronal Death ◽  
Measles Virus ◽  
Critical Role ◽  
Gamma Interferon ◽  
T Cell Response ◽  
Ifn Γ

ABSTRACT Neurons of the mammalian central nervous system (CNS) are an essential and largely nonrenewable cell population. Thus, virus infections that result in neuronal depletion, either by virus-mediated cell death or by induction of the cytolytic immune response, could cause permanent neurological impairment of the host. In a transgenic mouse model of measles virus (MV) infection of neurons, we have previously shown that the host T-cell response was required for resolution of infection in susceptible adult mice. In this report, we show that this protective response did not result in neuronal death, even during the peak of T-cell infiltration into the brain parenchyma. When susceptible mice were intercrossed with specific immune knockout mice, a critical role for gamma interferon (IFN-γ) was identified in protection against MV infection and CNS disease. Moreover, the addition of previously activated splenocytes or recombinant murine IFN-γ to MV-infected primary neurons resulted in the inhibition of viral replication in the absence of neuronal death. Together, these data support the hypothesis that the host immune response can promote viral clearance without concomitant neuronal loss, a process that appears to be mediated by cytokines.

Effect of Hydroxyurea Treatment on In Vitro Adhesion of Sickle Erythrocytes to Sickle Leukocyte Subpopulations.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 362-362
Author(s):  
Eileen M. Finnegan ◽  
Aslihan Turhan ◽  
Jennifer Gaines ◽  
David E. Golan ◽  
Gilda Barabino
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Sickle Cell Disease ◽  
Adhesion Molecules ◽  
Sickle Cell ◽  
Cell Disease ◽  
Tnf Α ◽  
Adhesive Interactions ◽  
Cell Cell

Abstract Microvascular vaso-occlusion in sickle cell disease is thought to involve adhesive interactions among erythrocytes (RBCs), leukocytes and vascular endothelial cells. Recent studies have demonstrated the presence of a significant inflammatory response in sickle cell disease, including changes in the cell surface adhesion molecules that mediate cell-cell interactions in the microvasculature. In this study, we used a parallel-plate flow chamber assay to determine the subpopulations of leukocytes that are involved in sickle leukocyte-RBC interactions. We also studied the effect of treatment with hydroxyurea (HU) on these adhesive interactions. Populations of monocytes, neutrophils (PMNs) and T cells were isolated by negative selection from the peripheral blood of untreated patients with sickle cell disease (SS), sickle patients receiving HU (SS-HU), and healthy control subjects (AA). Adhesive interactions involving these leukocyte subpopulations, human umbilical vein endothelial cells (HUVECs) pretreated with tumor necrosis factor-α (TNF-α ), and autologous RBCs were measured under a shear stress of 1 dyne/cm2. Compared to the corresponding cell populations from AA individuals, PMNs, monocytes, and T cells from SS individuals were significantly more adherent to TNF-α-treated HUVECs (774±59 vs. 502±27 cells/mm2, p=0.001; 533±66 vs. 348±36 cells/mm2, p=0.024; and 470±75 vs. 227±26 cells/mm2, p=0.009, respectively). HU therapy significantly decreased the adhesion of SS PMNs to HUVECs (774±59 cells/mm2 for SS vs. 604±36 for SS-HU, p=0.025). Compared to adherent AA leukocytes, adherent SS leukocytes exhibited greater participation in adhesive interactions with autologous RBCs (41±3% for SS vs. 27±3% for AA, p=0.002), and HU treatment decreased the fraction of leukocytes that captured autologous RBCs to the control level (29±3% for SS-HU, p=0.006 vs. SS). Compared to adherent PMNs from SS individuals, adherent PMNs from SS-HU individuals showed significantly reduced participation in the capture of RBCs (53±6% for SS vs. 35±5% for SS-HU, p=0.021). Although adherent T cells from SS individuals participated significantly more in RBC capture than adherent T cells from AA individuals (28±5% for SS vs. 10±2% for AA, p=0.007), HU therapy did not have a significant effect on this parameter (21±5% for SS-HU, p=0.373). Compared to AA leukocytes, SS leukocytes captured more RBCs per participating adherent leukocyte (2.8±0.2 vs. 1.9±0.1 RBCs/cell, p=0.001). HU therapy reduced the number of RBCs captured per PMN but not the number captured per T cell. Compared to AA T cells, SS T cells captured adherent RBCs for a significantly longer period of time (51±9 vs. 26±6 seconds, p=0.035). Our data suggest that sickle neutrophils, monocytes and T cells may all be involved in adhesive interactions with sickle RBCs. PMN-RBC and monocyte-RBC interactions appear to be more numerous than T cell-RBC interactions, although T cell-RBC interactions may be stronger. HU therapy appears to target PMN-RBC and monocyte-RBC interactions preferentially. Future studies will focus on the role of particular adhesion molecules in mediating these interactions and on the potential for therapeutic interventions targeting cell-cell adhesion.

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