Exacerbated intestinal inflammation in P2Y deficient mice is associated with Th17 activation.

Extracellular nucleotides are released as constitutive danger signals by various cell types and activate nucleotide (P2) receptors such as P2Y receptor. P2Y activation on monocytes induces the secretion of the chemokine CXCL8 which may propagate intestinal inflammation. Also, P2Y expression is increased in infiltrating T cells of Crohn's disease patients.

Alpha2beta1 Integrin (VLA-2) Protects Activated Human Effector T Cells From Methotrexate-Induced Apoptosis.

β1 integrins are critical for T cell migration, survival and costimulation. The integrin α2β1, which is a receptor for collagen, also named VLA-2, is a major costimulatory pathway of effector T cells and has been implicated in arthritis pathogenesis. Herein, we have examined its ability to promote methotrexate (MTX) resistance by enhancing effector T cells survival.

Human Th17 Migration in Three-Dimensional Collagen Involves p38 MAPK.

T cell migration across extracellular matrix (ECM) is an important step of the adaptive immune response but is also involved in the development of inflammatory autoimmune diseases. Currently, the molecular mechanisms regulating the motility of effector T cells in ECM are not fully understood. Activation of p38 MAPK has been implicated in T cell activation and is critical to the development of immune and inflammatory responses.

Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway.

Effector T cell migration through the tissue extracellular matrix (ECM) is an important step of the adaptive immune response and in the development of inflammatory diseases. However, the mechanisms involved in this process are still poorly understood. In this study, we addressed the role of a collagen receptor, the discoidin domain receptor 1 (DDR1), in the migration of Th17 cells.

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss.

Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin α2β1 (CD49b), and IL-7 increases their adhesion to collagen via α2β1 integrin.

α2β1 integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis.

Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA).

Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner.

The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly understood. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T-cells by up-regulating the expression and function of the ATP-binding cassette C 1 (ABCC1) transporter, also known as multidrug resistance-associated protein 1. We find that collagen but not fibronectin reduces intracellular doxorubicin content and up-regulates the expression levels of ABCC1.

α2β1 integrin promotes chemoresistance against doxorubicin in cancer cells through extracellular signal-regulated kinase (ERK).

The role and the mechanisms by which β1 integrins regulate the survival and chemoresistance of T cell acute lymphoblastic leukemia (T-ALL) still are poorly addressed. In this study, we demonstrate in T-ALL cell lines and primary blasts, that engagement of α2β1 integrin with its ligand collagen I (ColI), reduces doxorubicin-induced apoptosis, whereas fibronectin (Fn) had no effect. ColI but not Fn inhibited doxorubicin-induced mitochondrial depolarization, cytochrome c release, and activation of caspase-9 and -3.

Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway.

The expression and function of discoidin domain receptor 1 (DDR1) in T cells are still poorly explored. We have recently shown that activation of primary human T cells via their T cell receptor leads to increased expression of DDR1, which promoted their migration in three-dimensional collagen. In the present study, we provide evidence that activated T cells bind collagen through DDR1.

Cytohesin-1 regulates human blood neutrophil adhesion to endothelial cells through β2 integrin activation.

Cytohesin-1 is a guanine nucleotide exchange factor for ADP ribosylation factor 6 (Arf6) in human blood neutrophils and differentiated PLB-985 neutrophil-like cells. Cytohesin-1 regulates adhesion and the transendothelial migration of monocytes, dendritic cells and T lymphocytes through activation of the β2 integrin LFA-1. In this study we investigated the role of cytohesin-1 in neutrophil and neutrophil-like cell adhesion to HUVECs, immobilized ICAM-1, and the α4β1 and α5β1 integrin extracellular matrix ligand fibronectin.

Cytohesin-1 regulates fMLF-mediated activation and functions of the β2 integrin Mac-1 in human neutrophils.

The nucleotide exchange factor cytohesin-1 was previously reported to interact with the cytoplasmic domains of the integrin β-chain common to all β(2) integrins such as LFA-1 and Mac-1. We show here that cytohesin-1, which contributes to fMLF-induced functional responses in PMNs through activation of Arf6, restrains the activation of the β(2) integrin Mac-1 (αMβ(2)) in PMNs or dcAMP-differentiated PLB-985 cells. We found that the cytohesin-1 inhibitor SecinH3 or siRNA increased cell adhesion to immobilized fibrinogen and fMLF-mediated conformational changes of Mac-1, monitored using mAb CBRM1/5, specific for the activation epitope of the αM subunit.

An essential role for phospholipase D in the recruitment of vesicle amine transport protein-1 to membranes in human neutrophils.

Although phosphatidic acid (PA) regulates a wide variety of physiological processes, its targets remain poorly characterized in human neutrophils. By co-sedimentation with PA-containing vesicles we identified several PA-binding proteins including vesicle amine transport protein-1 (VAT-1), Annexin A3 (ANXA3), Rac2, Cdc42 and RhoG in neutrophil cytosol. Except for ANXA3, protein binding to PA-containing liposomes was calcium-independent.

Cytohesin-1 regulates the Arf6-phospholipase D signaling axis in human neutrophils: impact on superoxide anion production and secretion.

Polymorphonuclear neutrophil (PMN) stimulation with fMLP stimulates small G proteins such as ADP-ribosylation factors (Arfs) Arf1 and Arf6, leading to phospholipase D (PLD) activation and functions such as degranulation and the oxidative burst. However, the molecular links between fMLF receptors and PLD remain unclear. PMNs express cytohesin-1, an Arf-guanine exchange factor that activates Arfs, and its expression is strongly induced during the acquisition of the neutrophilic phenotype by neutrophil-like cells.

Characterisation of degranulation and phagocytic capacity of a human neutrophilic cellular model, PLB-985 cells.

Exocytosis of neutrophil granules is a major event that converts circulating neutrophils into fully activated cells capable of chemotaxis, phagocytosis and destruction of pathogens. The PLB-985 cell line is a suitable neutrophilic cellular model which is utilised to study the different functional responses of neutrophils. In this study, we characterised the differentiation of PLB-985 cells toward the granulocytic pathway, using three different inducing agents: dbcAMP, DMSO and DMF.