Potential role of indoleamine 2,3-dioxygenase in primary biliary cirrhosis.

Indoleamine 2,3-dioxygenase (IDO)-induced immunosuppression can be clinically beneficial for autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by autoimmune lesions of intrahepatic bile duct epithelial cells that may lead to irreversible cirrhosis or hepatocellular carcinoma. The present study assessed the expression and function of IDO in a cell culture model and in PBC patients.

αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.

Background And Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions.

CCL2 nitration is a negative regulator of chemokine-mediated inflammation.

Chemokines promote leukocyte recruitment during inflammation. The oxidative burst is an important effector mechanism, this leads to the generation of reactive nitrogen species (RNS), including peroxynitrite (ONOO). The current study was performed to determine the potential for nitration to alter the chemical and biological properties of the prototypical CC chemokine, CCL2.

Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

Purpose: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency.

Transplantation and inflammation: implications for the modification of chemokine function.

Oxidative stress is a major and recurring cause of damage during inflammation, especially following organ transplantation. Initial ischaemia-reperfusion injury causes the production of many reactive oxygen and nitrogen species, and subsequent recruitment and activation of inflammatory cells can lead to further oxidative stress. This stress is well known to cause damage at the cellular level, for example by induction of senescence leading to the production of a characteristic senescence-associated secretory phenotype.

Regulatory T cells inhibit CD8(+) T-cell tissue invasion in human skin graft-versus-host reactions.

Background: Regulatory T cells (Tregs) effectively ameliorate graft-versus-host disease (GVHD). The mechanisms underlying Treg therapeutic effect on GVHD are not fully elucidated. This study investigates whether Treg prevention of GVH tissue damage is associated with blocking CD8 effector T-cell tissue invasion, a question not yet addressed in humans.

Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation.

The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity.

The yin and yang of chemokine receptor activation.

Chemokines represent a class of cytokines that control the migration of leucocytes. The human chemokine system comprises 44 ligands and 21 receptors that have evolved to control leucocyte migration. Although chemokines are an attractive therapeutic target for anti-inflammatory intervention, clinical trials of small molecule receptor antagonists have failed to demonstrate efficacy.

Chemokines in transplantation: what can atypical receptors teach us about anti-inflammatory therapy?

More than 45 members of the family of chemotactic cytokines have been described. These chemokines control the migration of leukocytes throughout the whole alloimmune response from initial ischemic damage to acute inflammation and eventual resolution. Several chemokines have been strongly linked to allograft rejection.

Cardiac allograft rejection: examination of the expression and function of the decoy chemokine receptor D6.

Background: Inflammatory cell recruitment during allograft rejection is driven by a group of inflammatory cytokines termed chemokines. Chemokines are presented on the surface of the vascular endothelium where they ligate specific receptors expressed on the surface of leukocytes. Recently, a group of nonsignaling chemokine receptors have been described.

Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.

Unlabelled: Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis.

T cell extravasation: demonstration of synergy between activation of CXCR3 and the T cell receptor.

Endothelial cells present chemokines to T cells and can also stimulate the T cell antigen receptor by presentation of peptide-MHC antigen complexes. This study was designed to investigate the potential synergy between stimulation of the chemokine receptor CXCR3 and the human T cell receptor complex. Transendothelial T cell migration towards CXCL10 was modified by crosslinking CD3 immediately before addition to the endothelium.

Anti-inflammatory therapy by intravenous delivery of non-heparan sulfate-binding CXCL12.

Interaction between chemokines and heparan sulfate (HS) is essential for leukocyte recruitment during inflammation. Previous studies have shown that a non-HS-binding mutant form of the inflammatory chemokine CCL7 can block inflammation produced by wild-type chemokines. This study examined the anti-inflammatory mechanism of a non-HS-binding mutant of the homeostatic chemokine CXCL12.

Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2.

The chemokine receptor CCR2 binds four pro-inflammatory monocyte chemoattractant proteins, designated MCP1/CCL2, MCP2/CCL8, MCP3/CCL7 and MCP4/CCL13. This study demonstrates the important biology of this receptor during the response to the chemokine milieu. Competitive chemotaxis and calcium flux assays were performed utilising mixtures of chemokines to assess a hierarchal arrangement of chemokine prepotency; these demonstrated that the MCP2-CCR2 interaction is able to supersede signals generated by RANTES, another pro-inflammatory chemokine, or the homeostatic chemokine SDF1.

An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy.

Inflammation plays an important role in a wide range of human diseases. Chemokines are a group of proteins which control the migration and activation of the immune cells involved in all aspects of the inflammatory response. Chemokines bind to specific receptors of the seven-transmembrane spanning type on target leukocytes and also bind to cell-surface glycosaminoglycans (GAG).