scholarly journals Modulation of CXC Chemokine Receptor Expression and Function in Human Neutrophils during Aging In Vitro Suggests a Role in Their Clearance from Circulation

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Katja C. Weisel ◽  
Frank Bautz ◽  
Gabriele Seitz ◽  
Sedat Yildirim ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chemokine Receptor ◽  
Receptor Expression ◽  
Interleukin 8 ◽  
Polymorphonuclear Neutrophils ◽  
Human Neutrophils ◽  
Chemokine Receptor Expression ◽  
Chemokine Receptor Cxcr4 ◽  
Cxc Chemokine

In mice, differential regulation of CXC chemokine receptor expression in circulating polymorphonuclear neutrophils (PMNs) undergoing senescence results in homing to the bone marrow. However, the role of this compartment and of the chemokine receptor CXCR4 is still under discussion, and only scarce data exist about CXCR4 function in human PMN. In our study, we provide evidence that also in human neutrophils, expression (cell surface and mRNA), chemotactic and signaling functions of the homing-related chemokine receptor CXCR4 are upregulated during aging in vitro, independent of addition of stimulatory cytokines (TNF, IL-1, IL-8, G-CSF). In contrast, interleukin-8 receptors are downmodulated (CXCR2) or remain unchanged (CXCR1), suggesting that human PMNs undergoing senescence acquire a phenotype that impairs inflammatory extravasation and favors homing to the bone marrow or other tissues involved in sequestration. Partially retained responsiveness to interleukin-8 may be important for neutrophil function when senescence occurs after extravasation in inflamed tissues.

Effects of IL-8, Gro-α, and LTB4on the adhesive kinetics of LFA-1 and Mac-1 on human neutrophils

2001 ◽  
Vol 281 (5) ◽  
pp. C1568-C1578 ◽  
Author(s):  
Scott M. Seo ◽  
Larry V. McIntire ◽  
C. Wayne Smith
Keyword(s):  
Chemokine Receptor ◽  
Time Window ◽  
Interleukin 8 ◽  
Intercellular Adhesion Molecule ◽  
Human Neutrophils ◽  
Binding Characteristics ◽  
Topographical Distribution ◽  
Cxc Chemokine ◽  
Kinetics Of ◽  
Regulate Firm

Firm adhesion of rolling neutrophils on inflamed endothelium is dependent on β2(CD18)-integrins and activating stimuli. LFA-1 (CD11a/CD18) appears to be more important than Mac-1 (CD11b/CD18) in neutrophil emigration at inflammatory sites, but little is known of the relative binding characteristics of these two integrins under conditions thought to regulate firm adhesion. The present study examined the effect of chemoattractants on the kinetics of LFA-1 and Mac-1 adhesion in human neutrophils. We found that subnanomolar concentrations of interleukin-8, Gro-α, and leukotriene B4(LTB4) induced rapid and optimal rates of LFA-1-dependent adhesion of neutrophils to intercellular adhesion molecule (ICAM)-1-coated beads. These optimal rates of LFA-1 adhesion were transient and decayed within 1 min after chemoattractant stimulation. Mac-1 adhesion was equally rapid initially but continued to rise for ≥6 min after stimulation. A fourfold higher density of ICAM-1 on beads markedly increased the rate of binding to LFA-1 but did not change the early and narrow time window for the optimal rate of adhesion. Using well-characterized monoclonal antibodies, we showed that activation of LFA-1 and Mac-1 by Gro-α was completely blocked by anti-CXC chemokine receptor R2, but activation of these integrins by interleukin-8 was most effectively blocked by anti-CXC chemokine receptor R1. The topographical distribution of beads also reflected significant differences between LFA-1 and Mac-1. Beads bound to Mac-1 translocated to the cell uropod within 4 min, but beads bound to LFA-1 remained bound to the lamellipodial regions at the same time. These kinetic and topographical differences may indicate distinct functional contributions of LFA-1 and Mac-1 on neutrophils.

Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils

2007 ◽  
Vol 293 (2) ◽  
pp. C696-C704 ◽  
Author(s):  
Jia Sun ◽  
Raina Devi Ramnath ◽  
Madhav Bhatia
Keyword(s):  
Substance P ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Binding Activity ◽  
Receptor Expression ◽  
Chemokine Production ◽  
Chemokine Receptor Expression ◽  
Cc Chemokine ◽  
Primary Mouse ◽  
Cxc Chemokine

Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 μM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 μM) abolished SP-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation.

Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Taoyong Chen ◽  
Jun Guo ◽  
Mingjin Yang ◽  
Chaofeng Han ◽  
Minghui Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Chemokine Receptor ◽  
Cyclooxygenase 2 ◽  
Lymphoid Organs ◽  
Receptor Expression ◽  
Chemokine Receptor Expression ◽  
Cox 2 ◽  
Secondary Lymphoid Organs

Abstract Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow–derived DCs toward macrophage inflammatory protein-3β (MIP-3β) and induces them to retain responsiveness to MIP-1α after lipopolysaccharide (LPS)–stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor–κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.

scholarly journals Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation

2002 ◽  
Vol 196 (3) ◽  
pp. 311-321 ◽  
Author(s):  
Silvia F. Soriano ◽  
Patricia Hernanz-Falcón ◽  
José Miguel Rodríguez-Frade ◽  
Ana Martín de Ana ◽  
Ruth Garzón ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Nuclear Translocation ◽  
Receptor Expression ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Cxc Chemokine Receptor 4 ◽  
Trigger Receptor ◽  
Cxc Chemokine ◽  
Chemokine Receptor 4

Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and Gαi pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system.

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