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ABSTRACT: Asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus production, and variable airflow obstruction with airways hyperresponsiveness (AHR). In most cases the airway inflammation characteristic of asthma is thought to result from an allergic-type reaction to an inhaled substance from the environment (so-called allergic asthma). In allergic asthma, allergen exposure stimulates eosinophilic inflammation of the airways associated with infiltration of T cells. Although the recruitment of eosinophils into the airways is an important component in the pathogenesis of asthma, the trafficking of T lymphocytes into the airways is now believed to establish and orchestrate the asthmatic inflammatory response. This review explores the roles of various T cell subsets in the pathogenesis of allergic airway inflammation and highlights the contributions of these cells in regulating asthma.
Clinical & Experimental Allergy 01/2009; 38(12):1847-57. · 5.03 Impact Factor
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A D Luster
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ABSTRACT: Chemokines have emerged as critical regulators of leukocyte function and as such represent attractive new targets for the therapy of allergic diseases. Recent studies have revealed important roles for the chemokine family in both the afferent and efferent limbs of the immune system, orchestrating and integrating innate and acquired immune responses. A subset of chemokines including eotaxin-1 (also called CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), MCP (monocyte chemoattractant protein)-3 (CCL7), MCP (monocyte chemoattractant protein)-4 (CCL13), TARC (thymus- and activation-regulated chemokine) (CCL17), and MDC (macrophage-derived chemokine) (CCL22) are highly expressed in allergic inflammation and are regulated by T helper type 2 cytokines. Receptors for these chemokines, including CCR3 (CC chemokine receptor 3), CCR4 (CC chemokine receptor 4) and CCR8 (CC chemokine receptor 8) are expressed on key leukocytes associated with allergic inflammation, such as T helper type 2 cells, eosinophils, mast cells and basophils, establishing a subset of chemokine/chemokine receptors potentially important in allergic inflammation. Recent data using inhibitory antibodies and chemokine antagonists support the concept that interfering with this subset of chemokines and their receptors represents a new approach to allergy immunotherapy.
Current Opinion in Allergy and Clinical Immunology 01/2002; 1(6):561-7. · 4.11 Impact Factor
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ABSTRACT: Chemokine receptors are rapidly desensitized and internalized following ligand binding, a process that attenuates receptor-mediated responses. However, the physiological settings in which this process occurs are not clear. Therefore, we examined the fate of CXCR3, a chemokine receptor preferentially expressed on activated T cells following contact with endothelial cells. By immunofluorescence microscopy and flow cytometry, we found that CXCR3 was rapidly internalized when T cells were incubated with IFN-gamma-activated human saphenous vein endothelial cells (HSVEC), but not with resting HSVEC. Similar results were obtained using human CXCR3-transfected murine 300-19 B cells. CXCR3 down-regulation was significantly more pronounced when T cells were in contact with HSVEC than with their supernatants, suggesting that CXCR3 ligands were efficiently displayed on the surface of HSVEC. Using neutralizing mAbs to IFN-induced protein-10 (CXCL10), monokine induced by IFN-gamma (CXCL9), and IFN-inducible T cell alpha chemoattractant (I-TAC; CXCL11), we found that even though I-TAC was secreted from IFN-gamma-activated HSVEC to lower levels than IFN-induced protein-10 or the monokine induced by IFN-gamma, it was the principal chemokine responsible for CXCR3 internalization. This correlated with studies using recombinant chemokines, which revealed that I-TAC was the most potent inducer of CXCR3 down-regulation and of transendothelial migration. Known inhibitors of chemokine-induced chemotaxis, such as pertussis toxin or wortmannin, did not reduce ligand-induced internalization, suggesting that a distinct signal transduction pathway mediates internalization. Our data demonstrate that I-TAC is the physiological inducer of CXCR3 internalization and suggest that chemokine receptor internalization occurs in physiological settings, such as leukocyte contact with an activated endothelium.
The Journal of Immunology 01/2002; 167(12):7084-93. · 5.79 Impact Factor
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ABSTRACT: Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown.
The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR(23)) is substituted for the wild-type alanine (ALA(23)) at the 23rd amino acid at the terminus of the peptide leader sequence.
We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed.
Human 293 cells and PBMCs with THR(23) variant eotaxin secreted significantly less eotaxin protein than did ALA(23)-bearing cells. In the case-control study, THR(23)-THR(23) individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/microL; P < .05) than ALA(23)-ALA(23) subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR(23) eotaxin (percent of predicted FEV(1), 65% +/- 3.5% [THR(23)-THR(23)] vs 58% +/- 0.9% [THR(23)-ALA(23)] and 56% +/- 0.5% [ALA(23)-ALA(23)]; P < .05).
The THR(23) variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma.
Journal of Allergy and Clinical Immunology 12/2001; 108(6):946-53. · 11.00 Impact Factor
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ABSTRACT: To investigate the mechanisms of eosinophil recruitment in allergic airway inflammation, we examined the effects of interleukin (IL)-4, a Th2-type cytokine, on eotaxin and monocyte chemoattractant protein-4 (MCP-4) expression in human peripheral blood mononuclear cells (PBMCs; n = 10), in human lower airway mononuclear cells (n = 5), in the human lung epithelial cell lines A549 and BEAS-2B, and in human cultured airway epithelial cells. IL-4 inhibited eotaxin and MCP-4 mRNA expression induced by IL-1 beta and tumor necrosis factor-alpha in PBMCs but did not significantly inhibit expression in epithelial cells. Eotaxin and MCP-4 mRNA expression was not significantly induced by proinflammatory cytokines in lower airway mononuclear cells. IL-1 beta-induced eotaxin and MCP-4 protein production was also inhibited by IL-4 in PBMCs, whereas IL-4 enhanced eotaxin protein production in A549 cells. In contrast, dexamethasone inhibited eotaxin and MCP-4 expression in both PBMCs and epithelial cells. The divergent effects of IL-4 on eotaxin and MCP-4 expression between PBMCs and epithelial cells may create chemokine concentration gradients between the subepithelial layer and the capillary spaces that may promote the recruitment of eosinophils to the airway in Th2-type responses.
AJP Lung Cellular and Molecular Physiology 12/2001; 281(5):L1288-302. · 3.66 Impact Factor
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ABSTRACT: Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) mediate immunologic selection pressure by both cytolytic and noncytolytic mechanisms. Non cytolytic mechanisms include the release of beta-chemokines blocking entry of R5 HIV-1 strains. In addition, CD8(+) cells inhibit X4 virus isolates via release of as yet poorly characterized soluble factors. To further characterize these factors, we performed detailed analysis of CTL as well as bulk CD8(+) T lymphocytes from six HIV-1-infected individuals and from six HIV-1-seronegative individuals. Kinetic studies revealed that secreted suppressive activities of HIV-1-specific CTL and bulk CD8(+) T lymphocytes from all HIV-1-infected persons are significantly higher than that of supernatants from seronegative controls. The suppressive activity could be blocked by monensin and brefeldin A, was heat labile, and appeared in a pattern different from that of secretion of chemokines (MDC, I-309, MIP-1alpha, MIP-1beta, and RANTES), cytokines (gamma interferon, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor), and interleukins (interleukin-13 and interleukin-16). This suppression activity was characterized by molecular size exclusion centrifugation and involves a suppressive activity of >50 kDa which could be bound to heparin and a nonbinding inhibitory activity of <50 kDa. Our data provide a functional link between CD8(+) cells and CTL in the noncytolytic inhibition of HIV-1 and suggest that suppression of X4 virus is mediated through proteins. The sizes of the proteins, their affinity for heparin, and the pattern of release indicate that these molecules are not chemokines.
Journal of Virology 10/2001; 75(17):8306-16. · 5.40 Impact Factor
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ABSTRACT: The chemokine SDF-1 alpha (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1 alpha both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1 alpha are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1 alpha are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through G(alpha i) activation. In conclusion, SDF-1 alpha plays a role in two important processes of granule cell maturation - proliferation and migration - assisting in the achievement of appropriate cell number and position in the cerebellar cortex.
Development 07/2001; 128(11):1971-81. · 6.60 Impact Factor
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ABSTRACT: Chronic eosinophilic pneumonia (CEP) is characterized by chronic or recurrent pulmonary infiltrates with eosinophils, but the precise mechanism of eosinophil accumulation has not been fully elucidated. Eotaxin is one of the CC chemokines that selectively recruits eosinophils and contributes to the pathogenesis of allergic airway diseases including asthma, but its roles in pathogenesis of CEP have not been fully elucidated. The authors measured concentrations of eotaxin and other CC chemokines, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted, macrophage inflammatory protein-1alpha, and the eosinophil activating Th2 cytokine interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid from CEP patients (n=11), and compared these concentrations with those from control subjects (n = 6). The eotaxin (904 +/- 203 versus 29 +/- 7 pg x mL(-1), p = 0.0001), MCP-1 (194 +/- 57 versus 15 +/- 2 pg x mL(-1), p < 0.05), and IL-5 (7.8 +/- 2.0 versus 2.7 +/- 0.6 pg x mL(-1), p < 0.05) levels were significantly higher for cases with CEP in comparison to those serving as controls. Proportions of eosinophil and lymphocyte counts were greater in BAL fluid from CEP patients. Eotaxin and IL-5 levels correlated with the proportion of eosinophils in BAL fluid from CEP patients. MCP-1 correlated with the relative lymphocyte numbers. In short, eotaxin, interleukin-5, and monocyte chemoattractant protein-1 levels were higher in the BAL fluid of CEP patients and these levels may contribute to eosinophil and lymphocyte recruitment and activation in the airways as found with this disorder.
European Respiratory Journal 06/2001; 17(5):962-8. · 5.89 Impact Factor
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ABSTRACT: Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro-differentiated Stat6(+/+) antigen-specific Th2 cells were adoptively transferred into naive Stat6(-/-) and Stat6(+/+) mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6(+/+) mice, were dramatically absent in Stat6(-/)- mice that received Stat6(+/)+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.
Journal of Experimental Medicine 06/2001; 193(9):1087-96. · 13.85 Impact Factor
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ABSTRACT: Expression of pulmonary eotaxin protein and mRNA was determined in six subjects with atopic asthma and five nonatopic normal subjects. Levels of eotaxin expression and eosinophil mobilization were compared before and after segmental allergen challenge in subjects with atopic asthma. In the absence of allergen challenge, we found significantly higher levels of eotaxin in the bronchoalveolar lavage (BAL) fluid of subjects with asthma than in that of normal subjects (25 +/- 3 versus 15 +/- 2 pg/ml, p < 0.05). BAL eotaxin levels increased after segmental allergen challenge in all six subjects with atopic asthma tested, with a mean increase from 22 +/- 4 to 53 +/- 10 pg/ml (p = 0.013). Segmental allergen challenge was associated with a significant increase in the percentage of BAL macrophages and eosinophils that were immunopositive for eotaxin. Eotaxin mRNA was detectable by northern analysis in BAL cells exclusively from allergen-challenged segments. Allergen- induced increases in eotaxin levels were strongly associated with increases in BAL eosinophil recovery (r(2) = 0.88, p = 0.0036). Segmental allergen challenge also increased eotaxin expression in airway epithelial and endothelial cells obtained by endobronchial biopsy. These findings demonstrate, for the first time, that the airways of subjects with allergic asthma respond to allergen by increasing eotaxin expression. The tissue loci of eotaxin expression, the levels of eotaxin recovered in BAL fluid, and the association of eotaxin levels with eosinophil mobilization suggest either that eotaxin plays a mechanistic role in allergen-induced airway eosinophilia or that it serves as a biomarker for the causal mechanisms.
American Journal of Respiratory and Critical Care Medicine 06/2001; 163(7):1669-75. · 11.08 Impact Factor
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D Miotto,
P Christodoulopoulos,
R Olivenstein,
R Taha,
L Cameron,
A Tsicopoulos,
A B Tonnel,
O Fahy,
J J Lafitte, A D Luster,
B Wallaert,
C E Mapp,
Q Hamid
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ABSTRACT: Chemokines are involved in the influx of leukocytes into the airways in inflammatory lung diseases. The differential cell recruitment characteristic of T(H)1 versus T(H)2 immune responses may be associated with differential chemokine expression.
We investigated the expression of chemokines; monocyte chemotactic proteins (MCPs) 1, 3, and 4; eotaxin; and IFN-gamma-inducible protein 10 (IP-10) in both T(H)1- and T(H)2-mediated lung diseases.
By using immunocytochemistry and in situ hybridization, we examined the protein and mRNA expression, respectively, in bronchoalveolar lavage and biopsy samples in subjects with asthma, tuberculosis, sarcoidosis, and chronic bronchitis.
Increased immunoreactivity and mRNA expression of IP-10 and of the MCPs was found in the bronchoalveolar lavage fluid and biopsy specimens of subjects with asthma and tuberculosis compared with that of control subjects (P <.005). IP-10, however, was particularly increased in subjects with sarcoidosis (P <.001). Eotaxin, on the other hand, was increased only in patients with asthma when compared with control subjects (P <.005).
This study demonstrates that MCP-1, MCP-3, and MCP-4 expression is not specifically associated with lung diseases characterized by a particular cytokine profile. In contrast, IP-10 is mostly expressed in T(H)1-mediated diseases, and eotaxin expression seems to be specifically associated with lung diseases of a T(H)2 cytokine profile.
Journal of Allergy and Clinical Immunology 05/2001; 107(4):664-70. · 11.00 Impact Factor
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ABSTRACT: The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct CXCR-4 expression or signaling profiles. CD34(+) cells from BM were compared with blood: either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher levels of CXCR-4 surface expression on CD34(+) cells from blood sources, mobilized peripheral blood, or cord blood were observed compared with BM (p = 0.0005 and p = 0.002, respectively). However, despite lower levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by either calcium flux or transmigration was proportionally greatest in cells derived from BM. Further, internalization of CXCR-4 in response to ligand, associated with receptor desensitization, was significantly lower on BM-derived cells. Therefore, preserved chemokine receptor signaling was highly associated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the methionine-SDF-1beta analog that induces prolonged down-regulation/desensitization of CXCR-4 and observed mobilization of Lin(-), Sca-1(+), Thy-1(low), and c-kit(+) hemopoietic progenitor cells to the peripheral blood with a >30-fold increase compared with PBS control (p = 0.0007 day 1 and p = 0.004 day 2). These data demonstrate that CXCR-4 expression and function can be dissociated in progenitor cells and that desensitization of CXCR-4 induces stem cell entry into the circulation.
The Journal of Immunology 04/2001; 166(8):5027-33. · 5.79 Impact Factor
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ABSTRACT: While chemokines have received considerable attention for their role in leukocyte chemotaxis, their effects on platelets have not been well described. We found that two CC chemokine receptor 4 (CCR4) ligands, macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC) induce concentration-dependent platelet aggregation and calcium flux. Flow cytometric analysis revealed the expression of CCR4 on platelets and a monoclonal antibody (mAb) to CCR4 inhibited MDC- and TARC-induced platelet aggregation, confirming that this effect is mediated through their common receptor CCR4. MDC fully desensitized TARC-induced calcium mobilization in platelets, while TARC was unable to completely desensitize a subsequent MDC response, which is similar to observations made in Th2 CD4(+) lymphocytes and CCR4-transfected cells. Aspirin (ASA) treatment of platelets allowed reversible primary aggregation but inhibited irreversible complete aggregation, suggesting that MDC- and TARC-induced full platelet aggregation is dependent on cyclooxygenase metabolites of arachidonic acid. MDC and TARC were unable to induce platelet aggregation and platelet secretion in washed human platelets, even though they induced a calcium flux, suggesting that plasma components are required for MDC- and TARC-induced platelet aggregation. Since Th2-type cytokines induce the release of MDC and TARC from cells and the expression of these chemokines is increased in Th2-type inflammation, we hypothesize that MDC and TARC may play a role in platelet activation seen in Th2 diseases, such as asthma and atopic dermatitis.
Thrombosis Research 03/2001; 101(4):279-89. · 2.44 Impact Factor
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ABSTRACT: Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma. The only identified receptor for these two chemokines to date is the CCR2. To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2(-/-) mice with those of wild-type (WT) littermates following immunization and challenge with OVA. OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2(-/-) mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2(-/-) mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2(-/-) mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-gamma were also similar in WT and CCR2(-/-) mice. Finally, OVA/OVA CCR2(-/-) mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2.
The Journal of Immunology 01/2001; 165(11):6568-75. · 5.79 Impact Factor
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ABSTRACT: Eotaxin is an asthma-related C-C chemokine that is produced in response to interleukin-1beta (IL-1beta). We detected an increase in newly transcribed eotaxin mRNA in IL-1beta-stimulated airway epithelial cells. Transient transfection assays using promoter-reporter constructs identified a region as essential for IL-1beta-induced increases in eotaxin transcription. Using site-directed mutagenesis, we found that a nuclear factor-kappaB (NF-kappaB) site located 46 bp upstream from the transcriptional start site was both necessary and sufficient for IL-1beta induction of reporter construct activity. Electrophoretic mobility shift assay demonstrated that IL-1beta-stimulated airway epithelial cells produced p50 and p65 protein that bound this site in a sequence-specific manner. The functional importance of the NF-kappaB site was demonstrated by coexpression experiments in which increasing doses of p65 expression vector were directly associated with reporter activity exclusively in constructs with an intact NF-kappaB site (r(2) = 0.97, P = 0.002). Moreover, IL-1beta-induced increases in eotaxin mRNA expression are inhibited by inhibitors of NF-kappaB. Our findings implicate NF-kappaB and its binding sequence in IL-1beta-induced transcriptional activation of the eotaxin gene.
AJP Lung Cellular and Molecular Physiology 01/2001; 279(6):L1058-65. · 3.66 Impact Factor
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ABSTRACT: Monocyte recruitment to the central nervous system (CNS) is a necessary step in the development of pathologic inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Monocyte chemoattractant protein (MCP)-1, a potent agonist for directed monocyte migration, has been implicated in the pathogenesis of EAE. Here we report that deficiency in CC chemokine receptor (CCR)2, the receptor for MCP-1, confers resistance to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide 35-55 (MOGp35-55). CCR2(-/)- mice immunized with MOGp35-55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well the chemokine receptors CCR1, CCR2, and CCR5. Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. These data indicate that CCR2 plays a necessary and nonredundant role in the pathogenesis of EAE.
Journal of Experimental Medicine 11/2000; 192(7):1075-80. · 13.85 Impact Factor
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Journal of Laboratory and Clinical Medicine 09/2000; 136(2):87-92. · 2.62 Impact Factor
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ABSTRACT: Leukotriene B(4) (LTB(4)) is a potent chemoattractant active on multiple leukocytes, including neutrophils, macrophages, and eosinophils, and is implicated in the pathogenesis of a variety of inflammatory processes. A seven transmembrane-spanning, G protein-coupled receptor, called BLTR (LTB(4) receptor), has recently been identified as an LTB(4) receptor. To determine if BLTR is the sole receptor mediating LTB(4)-induced leukocyte activation and to determine the role of LTB(4) and BLTR in regulating leukocyte function in inflammation in vivo, we generated a BLTR-deficient mouse by targeted gene disruption. This mouse reveals that BLTR alone is responsible for LTB(4)-mediated leukocyte calcium flux, chemotaxis, and firm adhesion to endothelium in vivo. Furthermore, despite the apparent functional redundancy with other chemoattractant-receptor pairs in vitro, LTB(4) and BLTR play an important role in the recruitment and/or retention of leukocytes, particularly eosinophils, to the inflamed peritoneum in vivo. These studies demonstrate that BLTR is the key receptor that mediates LTB(4)-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB(4) in vivo.
Journal of Experimental Medicine 09/2000; 192(3):439-46. · 13.85 Impact Factor
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B Lamkhioued,
E A Garcia-Zepeda,
S Abi-Younes,
H Nakamura,
S Jedrzkiewicz,
L Wagner,
P M Renzi,
Z Allakhverdi,
C Lilly,
Q Hamid, A D Luster
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ABSTRACT: Chemokines are chemotactic cytokines that play an important role in recruiting leukocytes in allergic inflammation. Monocyte chemoacctractant protein (MCP)-4 is a CC chemokine with potent chemotactic activities for eosinophils, monocytes, T lymphocytes, and basophils and therefore represents a good candidate to participate in allergic reactions. To determine if MCP-4 plays a role in asthma, we have investigated the expression of MCP-4 messenger RNA (mRNA) and protein in the airways of patients with asthma and normal control subjects by in situ hybridization and immunohistochemistry. We found that MCP-4 mRNA and protein was significantly upregulated in the epithelium and submucosa of bronchial biopsies and in the bronchoalveolar lavage (BAL) cells of patients with asthma compared with normal control subjects (p < 0. 01). In addition, MCP-4 protein was significantly elevated in the BAL fluid of patients with atopic asthma when compared with normal control subjects (p < 0.01) and there was a significant correlation between MCP-4, eotaxin, and eosinophils. In support of our in situ findings demonstrating MCP-4 expression in epithelial cells and mononuclear cells in vivo, we have found that MCP-4 expression can be induced in these cells in vitro by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Interferon-gamma (IFN-gamma) acted synergistically with TNF-alpha and IL-1beta in the induction of mRNA MCP-4 mRNA expression in A549 cells, whereas the glucocorticoid dexamethasone diminished the cytokine-induced expression of MCP-4. Our findings demonstrate that MCP-4 is upregulated in the airways of patients with asthma and suggest that MCP-4 plays a role in the recruitment of eosinophils into the airways of patients with asthma.
American Journal of Respiratory and Critical Care Medicine 08/2000; 162(2 Pt 1):723-32. · 11.08 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor superfamily originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate inflammatory responses. Given the importance of endothelial cell (EC)-derived chemokines in regulating leukocyte function and trafficking, we studied the effects of PPARgamma ligands on the expression of chemokines induced in ECs by the Th1 cytokine IFN-gamma. Treatment of ECs with PPARgamma activators significantly inhibited IFN-gamma-induced mRNA and protein expression of the CXC chemokines IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), whereas expression of the CC chemokine monocyte chemoattractant protein-1 was not altered. PPARgamma activators decreased IFN-inducible protein of 10 kDa promoter activity and inhibited protein binding to the two NF-kappaB sites but not to the IFN-stimulated response element ISRE site. Furthermore, PPARgamma ligands inhibited the release of chemotactic activity for CXC chemokine receptor 3 (CXCR3)-transfected lymphocytes from IFN-gamma-stimulated ECs. These data suggest that anti-diabetic PPARgamma activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation.
The Journal of Immunology 07/2000; 164(12):6503-8. · 5.79 Impact Factor
